Rhino Log Yep Os 2007

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Corrected version: October 11, 2007
S U P P L E M E N T
Rhinology supplement 20 EPOS 2007
EPOS
3
2 0
2007
European Position Paper on

Rhinosinusitis and Nasal Polyps 2007
Wytske Fokkens, Valerie Lund, Joaquim Mullol, on behalf of the
European Position Paper on Rhinosinusitis and Nasal Polyps group.
International
Rhinology
Rhinologie
Internationale
ABSTRACT
W.J. Fokkens, V.J. Lund, J. Mullol et al., European Position Paper on Nasal Polyps 2007.
Rhinology 45; suppl. 20: 1-139.
* corresponding author: Wytske Fokkens, Department of Otorhinolaryngology, Amsterdam Medical Centre, PO box 22660, 1100 DD Amsterdam,
The Netherlands. Email: w.j.fokkens@amc.nl
Rhinosinusitis is a significant and increasing health problem which results in a large financial burden on society. This evidence based
position paper describes what is known about rhinosinusitis and nasal polyps, offers evidence based recommendations on diagnosis
and treatment, and considers how we can make progress with research in this area.
Rhinitis and sinusitis usually coexist and are concurrent in most individuals; thus, the correct terminology is now rhinosinusitis.
Rhinosinusitis (including nasal polyps) is defined as inflammation of the nose and the paranasal sinuses characterised by two or more
symptoms, one of which should be either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip),
facial pain/pressure, reduction or loss of smell; and either endoscopic signs of polyps and/or mucopurulent discharge primarily
from middle meatus and/or; oedema/mucosal obstruction primarily in middle meatus, and/or CT changes showing mucosal changes
within the ostiomeatal complex and/or sinuses.
The paper gives different definitions for epidemiology, first line and second line treatment and for research.
Furthermore the paper describes the anatomy and (patho)physiology, epidemiology and predisposing factors, inflammatory mechanisms, evidence based diagnosis, medical and surgical treatment in acute and chronic rhinosinusitis and nasal polyposis in adults and
children. Evidence based schemes for diagnosis and treatment are given for the first and second line clinicians. Moreover attention is
given to complications and socio-economic cost of chronic rhinosinusitis and nasal polyps. Last but not least the relation to the lower
airways is discussed.
Supplement 20
Participants:
Wytske Fokkens, Chair. Department of Otorhinolaryngology,
Amsterdam Medical Centre, Amsterdam
Valerie Lund, Co-Chair. Institute of Laryngology and
Otolaryngology. University College London, London
Joaquim Mullol, Co-Chair. Rhinology Unit & Smell Clinic, ENT
Department, Hospital Clnic IDIBAPS, Barcelona, Spain
Claus Bachert. Upper Airway Research Laboratory, Department
of Otorhinolaryngology, Ghent University, Belgium
Noam Cohen, Department of Otorhinolaryngology: Head and
Neck Surgery, University of Pennsylvania, Philadelphia, USA
Roxanna Cobo, Department of Otolaryngology, Centro
Mdico Imbanaco, Cali, Colombia
Martin Desrosiers, Department of Otolaryngology-Head and
Neck Surgery, University of Montreal, Montreal, Canada
Peter Hellings, Department of Otorhinolaryngology, University
Hospitals Leuven
Catholic University Leuven, Leuven, Belgium
Mats Holmstrom, Department of Otorhinolaryngology,
Uppsala University Hospital Uppsala, Sweden
Maija Hytnen, Department of Otorhinolaryngology, Helsinki
University Central Hospital, Helsinki, Finland
Nick Jones, Department of Otorhinolaryngology, Head and
Neck Surgery, Queen's Medical Centre, University of
Nottingham, Nottingham, UK
Livije Kalogjera, Department of Otorhinolaryngology/Head
and Neck Surgery, University Hospital "Sestre Milosrdnice",
Zagreb, Croatia
David Kennedy, Department of Otorhinolaryngology: Head and
Neck Surgery, University of Pennsylvania, Philadelphia, USA
Jean Michel Klossek, Department ENT and Head and neck
surgery, CHU Poitiers : Univ Poitiers Hopital Jean Bernard,
Poitiers, France
Marek Kowalski, Department of Immunology, Rheumatology

and Allergy, Medical University of Lodz, Lodz, Poland
Eli Meltzer, Allergy and Asthma Medical Group and Research
Center, University of California at San Diego, San Diego,
California
Bob Naclerio, Section of Otolaryngology-Head and Neck
Surgery, The Pritzker School of Medicine, The University of
Chicago, Chicago, USA
Desiderio Passali, ENT Department, Policlinico Le Scotte University of Siena, Siena, Italy
David Price, Dept of General Practice and Primary Care,
University of Aberdeen, Aberdeen, UK
Herbert Riechelmann, University Hospital for Ear, Nose and
Throat Diseases, University Hospital Center Ulm, Ulm,
Germany
Glenis Scadding, Allergy & Medical Rhinology Department,
Royal National TNE Hospital, London, UK.
Heinz Stammberger, University Ear, Nose and Throat
Hospital, Graz, Austria
Mike Thomas, Department of General Practice and Primary
Care, University of Aberdeen, Aberdeen, UK
Richard Voegels, Rhinology - Clinics, University of Sao Paulo
Medical School, Sao Paulo, Brazil
De-Yun Wang. Department of Otolaryngology, National
University of Singapore, Singapore
Acknowledgements:
The chairs of EP3OS would like to express their gratitude for
the great help in preparing this document:
Fenna Ebbens, Amsterdam
Christos Georgalas, London
Hanneke de Bakker, Amsterdam
Josep Maria Guilemany, Barcelona
European Position Paper on Rhinosinusitis and Nasal Polyps 2007

CONTENTS
1
Introduction
2
2-1
2-2
2-3
Definition of rhinosinusitis and nasal polyps

Introduction
Clinical definition
Definition for use in epidemiology studies/
General Practice
2-4 Definition for research
6
7
3
3-1
3-2
3-3
Chronic rhinosinusitis with or without nasal polyps

Anatomy and (patho)physiology
Rhinosinusitis
8
8
8
8
4
4-1
4-2
4-3
4-4
4-5
Epidemiology and predisposing factors

Introduction.
Acute bacterial rhinosinusitis.
Factors associated with acute rhinosinusitis.
Chronic rhinosinusitis (CRS) without nasal polyps
Factors associated with chronic rhinosinusitis (CRS)
without nasal polyps
Chronic rhinosinusitis with nasal polyps
Factors associated with Chronic rhinosinusitis
with nasal polyps
Epidemiology and predisposing factors for
rhinosinusitis in children
Conclusion
10
10
10
10
12
4-6
4-7
4-8
4-9
5
5-6
Inflammatory mechanisms in acute and chronic

rhinosinusitis with or without nasal polyposis
Introduction
Acute rhinosinusitis
Chronic rhinosinusitis without nasal polyps
Chronic rhinosinusitis with nasal polyps
Aspirin sensitivity Inflammatory mechanisms in
acute and chronic rhinosinusitis
Conclusion
6
6-1
6-2
6-3
Diagnosis
Assessment of rhinosinusitis symptoms
Examination
Quality of Life
5-1
5-2
5-3
5-4
5-5
7
7-1
7-2
7-3
7-4
7-5
Management
Treatment of rhinosinusitis with corticosteroids
Treatment of rhinosinusitis with antibiotics
Other medical management for rhinosinusitis
Evidence based surgery for rhinosinusitis
Influence of age concomitant diseases on sinus
surgery outcome
7-6 Complications of surgical treatment
6
6
6
8
8-1
8-2
8-3
8-4
8-5
8-6
8-7
Complications of rhinosinusitis and nasal polyps

Introduction
Epidemiology of complications
Orbital complications
Endocranial complications
Cavernous sinus thrombosis
Osseous complications
Unusual complications of rhinosinusitis
80
80
80
80
01
82
82
83
9
9-1
9-2
9-3
9-4
9-5
9-6
9-7
Special considerations: Rhinosinusitis in children

Introduction
Anatomy
Epidemiology and pathophysiology
Symptoms and signs
Clinical examination
Investigations
Management
84
84
84
84
85
85
85
87
10

in relation to the lower airways
Introduction
Asthma and Chronic Rhinosinusitis without NP
Asthma and Chronic Rhinosinusitis with NP
COPD and rhinosinusitis
90
90
90
91
91
12
15
10-1
10-2
10-3
10-4
16
11
18
18
19
19
19
20
26
32
34
35
35
37
40
43
43
51
56
64
71
76
Socio-economic cost of chronic rhinosinusitis and

nasal polyps
11-1 Direct Costs
11-2 Indirect Costs
92
92
92
12
94
Outcomes measurements in research
13
13-1
13-2
13-3
Evidence based schemes for diagnostic and treatment

Introduction
Introduction
Evidence based management scheme for adults with
acute rhinosinusitis
13-4 Evidence based management scheme for adults with
chronic rhinosinusitis without nasal polyps
13-5 Evidence based schemes for therapy in children
95
95
97
14 Research needs and priorities

14-1 Epidemiology: Identifying the risk factors for
development of CRS an NP
14-2 Beyond infection: New roles for bacteria
14-3 Host response
14-4 Genetics
14-5 Clinical trials
105
15
107
GLOSARRY TERMS
98
100
103
105
105
105
105
105
16 Information on QOL instruments:

16-1 General health status instruments:
16-2 Disease specific health status instruments:
108
108
108
17
Survey of published olfactory tests
109
18
References
111
Supplement 20
1. Introduction
Rhinosinusitis is a significant health problem which seems to
mirror the increasing frequency of allergic rhinitis and which
results in a large financial burden on society (1-3). Data on
(chronic) rhinosinusitis are limited and the disease entity is
badly defined. Therefore, the available data are difficult to
interpret and extrapolate.
The last decade has seen the development of a number of
guidelines, consensus documents and position papers on the
epidemiology, diagnosis and treatment of rhinosinusitis and
nasal polyposis (4-7). In 2005 the first European Position Paper
on Rhinosinusitis and Nasal Polyps (EP3OS) was published (8, 9).
This first evidence based position paper was initiated by the
European Academy of Allergology and Clinical Immunology
(EAACI) to consider what was known about rhinosinusitis and
nasal polyps, to offer evidence-based recommendations on
diagnosis and treatment, and to consider how we can make
progress with research in this area. The paper has been
approved by the European Rhinologic Society.
Evidence-based medicine is an important method of preparing
guidelines (10, 11). Moreover, the implementation of guidelines is
equally important.
Table 1-1. Category of evidence (11)
Ia
Ib
IIa
IIb
III
IV
evidence from meta-analysis of randomised controlled trials

evidence from at least one randomised controlled trial
evidence from at least one controlled study without
randomisation
evidence from at least one other type of quasi-experimental study
evidence from non-experimental descriptive studies, such as
comparative studies, correlation studies, and case-control studies
evidence from expert committee reports or opinions or clinical
experience of respected authorities, or both
Table 1-2. Strength of recommendation

A
B
C
D
directly based on category I evidence

directly based on category II evidence or extrapolated
recommendation from category I evidence
directly based on category III evidence or extrapolated
recommendation from category I or II evidence
directly based on category IV evidence or extrapolated
recommendation from category I, II or III evidence
Since the preparation of the first EP3OS document an increasing amount of evidence on the pathophysiology, diagnosis and
treatment has been published (figure 1).
Figure 1. Randomized controlled trials in chronic rhinosinusitis with
or without nasal polyps. The number of trials in the last 5-6 years
equals the number ever published before.
This revision is intended to be a state-of-the art review for the

specialist as well as for the general practitioner:
to update their knowledge of rhinosinusitis and nasal polyposis;
to provide an evidence-based documented review of the
diagnostic methods;
to provide an evidence-based review of the available treatments;
to propose a stepwise approach to the management of the
disease;
to propose guidance for definitions and outcome measurements in research in different settings.
In this revision new data have led to considerable increase in
amount of available evidence and therefore to considerable
changes in the schemes for diagnosis and treatment.
Moreover the whole document has been made more consistent,
some chapters are significantly extended and others are added.
Last but not least contributions from many other part of the
world have attributed to our knowledge and understanding.
Supplement 20
2. Definition of rhinosinusitis and nasal polyps

2-1 Introduction
Rhinitis and sinusitis usually coexist and are concurrent in most
individuals; thus, the correct terminology is now rhinosinusitis.
The diagnosis of rhinosinusitis is made by a wide variety of
practitioners, including allergologists, otolaryngologists, pulmonologists, primary care physicians and many others. Therefore,
an accurate, efficient, and accessible definition of rhinosinusitis
is required. A number of groups have published reports on rhinosinusitis and its definition. In most of these reports definitions are based on symptomatology and duration of disease and
a single definition is aimed at all practitioners (4, 5, 12, 13).
Due to the large differences in technical possibilities to diagnose and treat rhinosinusitis/nasal polyps by various disciplines, the need to differentiate between subgroups varies. On
one hand the epidemiologist wants a workable definition that
does not impose too many restrictions to study larger populations. On the other hand researchers in a clinical setting are in
need of a set of clearly defined items that describes their
patient population accurately and avoids the comparison of
apples and oranges in studies that relate to diagnosis and
treatment. The taskforce tried to accommodate these different
needs by offering definitions that can be applied in different
circumstances. In this way the taskforce hopes to improve the
comparability of studies, thereby enhancing the evidence
based diagnosis and treatment of patients with rhinosinusitis
and nasal polyps.
2-2-2 Severity of the disease

The disease can be divided into MILD, MODERATE and
SEVERE based on total severity visual analogue scale (VAS)
score (0 10 cm):
MILD
=
VAS 0-3
MODERATE
=
VAS >3-7
SEVERE
=
VAS >7-10
To evaluate the total severity, the patient is asked to indicate
on a VAS the answer to the question:
HOW TROUBLESOME ARE YOUR SYMPTOMS OF RHINOSINUSITIS?
A VAS > 5 affects patient QOL (14).

2-2-3 Duration of the disease
Acute
< 12 weeks
complete resolution of symptoms.
Chronic
>12 weeks symptoms
without complete resolution of symptoms.
Chronic rhinosinusitis may also be subject to exacerbations
2-2 Clinical definition
2-3 Definition for use in epidemiology studies/General Practice
2-2-1 Clinical definition of rhinosinusitis/nasal polyps
For epidemiological studies the definition is based on symptomatology without ENT examination or radiology.
2-2-1-1 Bacteria
Rhinosinusitis (including nasal polyps) is defined as:
inflammation of the nose and the paranasal sinuses characterised by two or more symptoms, one of which should be
either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip):
- facial pain/pressure,
- reduction or loss of smell;
and either
endoscopic signs of:
- polyps and/or;
- mucopurulent discharge primarily from middle meatus
and/or; oedema/mucosal obstruction primarily in middle meatus,
and/or
CT changes:
- mucosal changes within the ostiomeatal complex and/or
sinuses.
Acute rhinosinusitis (ARS) is defined as:

sudden onset of two or more symptoms, one of which should
be either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip):
facial pain/pressure,
reduction or loss of smell;
for <12 weeks;
with symptom free intervals if the problem is recurrent;
with validation by telephone or interview.
Questions on allergic symptoms i.e. sneezing, watery rhinorrhea, nasal itching and itchy watery eyes should be included.
Acute rhinosinusistis can occur once or more than once in a
defined time period. This is usually expressed as episodes/year
but there must be complete resolution of symptoms between episodes for it to constitute genuine recurrent acute rhinosinusitis.
Common cold/ acute viral rhinosinusitis is defined as:

duration of symptoms for less than 10 days.
Acute non-viral rhinosinusitis is defined as:
increase of symptoms after 5 days or persistent symptoms after
10 days with less than 12 weeks duration.
Chronic rhinosinusitis with or without nasal polyps is defined as:
presence of two or more symptoms one of which should be
either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip):
facial pain/pressure;
for >12 weeks;
with validation by telephone or interview.
Questions on allergic symptoms i.e. sneezing, watery rhinorrhea, nasal itching and itchy watery eyes should be included.
2-4 Definition for research
For research purposes acute rhinosinusitis is defined as above.
Bacteriology (antral tap, middle meatal tap) and/or radiology
(X-ray, CT) are advised, but not obligatory.
For research purposes chronic rhinosinusitis (CRS) is defined
as above. CRS is the major finding and nasal polyposis (NP) is
considered a subgroup of this entitiy. For the purpose of a
study, the differentiation between CRS and NP must be based
on out-patient endoscopy. The research definition is based on
the presence of polyps and prior surgery.
2-4-1 Definition of chronic rhinosinusitis when no earlier sinus
surgery has been performed
Chronic rhinosinusitis with nasal polyposis:
polyps bilateral, endoscopically visualised in middle meatus
Chronic rhinosinusitis without nasal polyps:
no visible polyps in middle meatus, if necessary following
decongestant
This definition accepts that there is a spectrum of disease in

CRS which includes polypoid change in the sinuses and/or
middle meatus but excludes those with polypoid disease presenting in the nasal cavity to avoid overlap.
2-4-2 Definition of chronic rhinosinusitis when sinus surgery has
been performed
Once surgery has altered the anatomy of the lateral wall, the
presence of polyps is defined as bilateral pedunculated lesions
as opposed to cobblestoned mucosa > 6 months after surgery
on endoscopic examination. Any mucosal disease without
overt polyps should be regarded as CRS.
2-4-3 Conditions for sub-analysis
The following conditions should be considered for sub-analysis:
1. aspirin sensitivity based on positive oral, bronchial or nasal
provocation or an obvious history;
2. asthma/bronchial hyper-reactivity /COPD/ bronchiectasies
based on symptoms, respiratory function tests;
3. allergy based on specific serum IgE or SPTs.
2-4-4 Exclusion from general studies
Patients with the following diseases should be excluded from
general studies, but may be the subject of a specific study on
chronic rhinosinusitis and/or nasal polyposis:
1. cystic fibrosis based on positive sweat test or DNA alleles;
2. gross immunodeficiency (congenital or acquired);
3. congenital mucociliary problems eg primary ciliary dyskinesia (PCD);
4. non-invasive fungal balls and invasive fungal disease;
5. systemic vasculitis and granulomatous diseases;
6. cocaine abuse;
7. neoplasia.
Supplement 20
3. Chronic rhinosinusitis with or without nasal polyps

3-1 Anatomy and (patho)physiology
The nose and paranasal sinuses constitute a collection of airfilled spaces within the anterior skull. The paranasal sinuses
communicate with the nasal cavity through small apertures.
The nasal cavity and its adjacent paranasal sinuses are lined by
pseudostratified columnar ciliated epithelium. This contains
goblet cells and nasal glands, producers of nasal secretions that
keep the nose moist and form a tapis roulant of mucus.
Particles and bacteria can be caught in this mucus, rendered
harmless by enzymes like lysozyme and lactoferrin, and be
transported down towards the oesophagus. Cilia play an important role in mucus transport. All paranasal sinuses are normally
cleared by this mucociliary transport, even though transport
from large areas of sinuses passes through small openings
towards the nasal cavity.
A fundamental role in the pathogenesis of rhinosinusitis is
played by the ostiomeatal complex, a functional unit that comprises maxillary sinus ostia, anterior ethmoid cells and their
ostia, ethmoid infundibulum, hiatus semilunaris and middle
meatus. The key element is the maintenance of the ostial
patency. Specifically, ostial patency significantly affects mucus
composition and secretion; moreover, an open ostium allows
mucociliary clearance to easily remove particulate matter and
bacteria. Problems occur if the orifice is too small for the
amount of mucus, if mucus production is increased, for
instance during an upper respiratory tract infection (URTI), or
if ciliary function is impaired. Stasis of secretions follows and
bacterial export ceases, causing or exacerbating inflammation
of the mucosa whilst aeration of the mucosa is decreased,
causing even more ciliary dysfunction. This vicious cycle can
be difficult to break, and if the condition persists, it can result
as chronic rhinosinusitis. In chronic rhinosinusitis the role of
ostium occlusion seems to be less pronounced than in ARS.
tional unit that comprises maxillary sinus ostia, anterior ethmoid cells and their ostia, ethmoid infundibulum, hiatus semilunaris and middle meatus. The key element is the maintenance of the ostial patency. An in depth discussion on factors
contributing to chronic rhinosinusitis and nasal polyps can be
found in chapter 4.
3-3 Chronic rhinosinusitis with or without nasal polyps
Chronic rhinosinusitis with or without nasal polyps is often
taken together as one disease entity, because it seems impossible to clearly differentiate both entities (22-24). Chronic rhinosinusitis with nasal polyps (CRS without NP) is considered a
subgroup of chronic rhinosinusitis (CRS) (fig. 3-1).
The question remains as to why ballooning of mucosa develops in polyposis patients and not in all rhinosinusitis patients.
Nasal polyps have a strong tendency to recur after surgery even
when aeration is improved (25). This may reflect a distinct property of the mucosa of polyp patients which has yet to be identified. Some studies have tried to divide chronic rhinosinusitis
and nasal polyps based on inflammatory markers (26-30) .
Although these studies point to a more pronounced eosinophilia and IL-5 expression in nasal polyps than that found in
patients with chronic rhinosinusitis, these studies also point to
a continuum in which differences might be found at the ends
of the spectrum but at the moment no clear cut division can be
made.
Figure 3-1. The spectrum of chronic rhinosinusitis and nasal polyps
3-2 Rhinosinusitis
Rhinosinusitis is an inflammatory process involving the
mucosa of the nose and one or more sinuses. The mucosa of
the nose and sinuses form a continuum and thus more often
than not the mucous membranes of the sinus are involved in
diseases which are primarily caused by an inflammation of the
nasal mucosa. Chronic rhinosinusitis is a multifactorial disease
(15)
. Factors contributing can be mucociliairy impairment (16, 17),
(bacterial) infection (18), allergy (19), swelling of the mucosa for
another reason, or rarely physical obstructions caused by morphological/anatomical variations in the nasal cavity or
paranasal sinuses (20, 21). A role in the pathogenesis of rhinosinusitis is certainly played by the ostiomeatal complex, a func-
Nasal polyps appear as grape-like structures in the upper nasal

cavity, originating from within the ostiomeatal complex. They
consist of loose connective tissue, oedema, inflammatory cells
and some glands and capillaries, and are covered with varying
types of epithelium, mostly respiratory pseudostratified epithelium with ciliated cells and goblet cells. Eosinophils are the
most common inflammatory cells in nasal polyps, but neutrophils, mast cells, plasma cells, lymphocytes and monocytes
are also present, as well as fibroblasts. IL-5 is the predominant
cytokine in nasal polyposis, reflecting activation and prolonged
survival of eosinophils (31).
The reason why polyps develop in some patients and not in

others remains unknown. There is a definite relationship in
patients with 'Samter triad': asthma, NSAID sensitivity and
nasal polyps. However, not all patients with NSAID sensitivity
have nasal polyps, and vice-versa. In the general population,
the prevalence of nasal polyps is 4% (32). In patients with asthma, a prevalence of 7 to 15% has been noted whereas, in
NSAID sensitivity, nasal polyps are found in 36 to 60% of
patients (33, 34). It had long been assumed that allergy predisposed to nasal polyps because the symptoms of watery rhinorrhoea and mucosal swelling are present in both diseases, and
eosinophils are abundant. However, epidemiological data provide no evidence for this relationship: polyps are found in 0.5
to 1.5% of patients with positive skin prick tests for common
allergens (34, 35).
10
Supplement 20
4. Epidemiology and predisposing factors

4-1 Introduction
Rhinosinusitis in its many forms, constitutes one of the commonest conditions encountered in medicine and may present
to a wide range of clinicians from primary care to accident and
emergency, pulmonologists, allergists, otorhinolaryngologists
and even intensivists and neurosurgeons when severe complications occur.
The incidence of acute viral rhinosinusitis (common cold) is
very high. It has been estimated that adults suffer 2 to 5 colds
per year, and school children may suffer 7 to 10 colds per year.
The exact incidence is difficult to measure because most
patients with common cold do not consult a doctor. Recently a
case control study in the Dutch population concluded that an
estimated 900,000 consultations take place annually for acute
respiratory tract infection. Rhinovirus (24%) and Influenzae
(11%) were the most common agents isolated. (36). More reliable
data are available on ARS. As mentioned earlier acute nonviral rhinosinusitis (ARS) is defined as an increase of symptoms after 5 days or persistent symptoms after 10 days after a
sudden onset of two or more of the symptoms: nasal blockage/congestion, anterior discharge/postnasal drip, facial
pain/pressure, and/or reduction/loss of smell. It is estimated
that only 0.5% to 2% of viral URTIs are complicated by bacterial infection; however, the exact incidence is unknown given
the difficulty distinguishing viral from bacterial infection without invasive sinus-puncture studies. Bacterial culture results in
suspected cases of acute community-acquired sinusitis are positive in only 60% of cases (37). Signs and symptoms of bacterial
infection may be mild and often resolve spontaneously (38, 39).
In spite of the high incidence of ARS and prevalence and significant morbidity of chronic rhinosinusitis (CRS), with and without
nasal polyps, there is only limited accurate data on the epidemiology of these conditions. This observation mainly relates to the
lack of a uniformly accepted definition for CRS. In addition,
patient selection criteria greatly differ between epidemiologic
studies complicating comparison of studies. When interpreting
epidemiologic data, one should be aware of a significant selection bias of the different studies presented below. The purpose
of this section of the EP3OS document is to give an updated
overview of the currently available epidemiologic data on ARS
and CRS with and without nasal polyps, and illustrate the factors which are believed to predispose to their development.
condition. For example in the Cochrane Review on antibiotics

for ARS, studies were included if sinusitis was proven by a consistent clinical history, and radiographic or aspiration evidence
of ARS (40). However, most guidelines on the diagnosis of acute
bacterial rhinosinusitis base the diagnosis on symptoms and
clinical examination. However, if the diagnosis is based on clinical examination alone, the rate of false positive results is high.
In patients with a clinical diagnosis of ARS, less than half have
significant abnormalities at X-ray examination (41). Based on
sinus puncture/aspiration (considered the most accurate), 4983% of symptomatic patients had ARS (42). Compared with
puncture/aspiration, radiography offered moderate ability to
diagnose sinusitis Using sinus opacity or fluid as the criterion
for sinusitis, radiography had sensitivity of 0.73 and specificity
of 0.80 (42).
An average of 8.4 % of the Dutch population reported at least
one episode of ARS per year in 1999 (43). The incidence of visits
to the general practitioner for acute sinusitis in the
Netherlands in 2000 was 20 per 1,000 men and 33.8 per 1,000
women (44). According to National Ambulatory Medical Care
Survey (NAMCS) data in the USA, sinusitis is the fifth most
common diagnosis for which an antibiotic is prescribed.
Written in 2002, sinusitis accounted for 9% and 21% of all paediatric and adult antibiotic prescriptions respectively (4).
4-3 Factors associated with acute rhinosinusitis.
4-3-1 Pathogens
Superinfection by bacteria on mucosa damaged by viral infection (common cold) is the most important cause of ARS. The
most common bacterial species isolated from the maxillary
sinuses of patients with ARS are Streptococcus pneumoniae,
Haemophilus influenzae, and Moraxella catarrhalis, the latter
being more common in children (45, 46). Other streptococcal
species, anaerobic bacteria and Staphylococcus aureus cause a
small percentage of cases. Resistance patterns of the predominant pathogens vary considerably (47, 48). The prevalence and
degree of antibacterial resistance in common respiratory
pathogens are increasing worldwide. In France, increases in
resistance have been observed during the last twenty years in
the same geographical area for H influenzae and S pneumoniae(49). The association between inappropriate antibiotic consumption and the prevalence of resistance is widely assumed
based on in vitro experience (50). Pathogens may also influence
the severity of symptomatology (51).
4-2 Acute bacterial rhinosinusitis.

When describing the incidence of acute bacterial rhinosinusitis
there has been a lot of debate about the actual definition of the
4-3-2 Ciliary impairment

Normal mucociliary flow is a significant non-specific defence
mechanism in the prevention of ARS. Viral rhinosinusitis
11
results in the loss of cilia and ciliated cells, reaching a maximum around one week after the infection. Three weeks after
the beginning of the infection the number of cilia and ciliated
cells increases to nearly normal. However, as a sign of regeneration, immature short cilia (0.7 to 2.5 m in length) were often
seen (52). The impaired mucociliary function during viral rhinosinusitis results in an increased sensitivity to bacterial infection.
al. reported that whilst 39% of patients with CRS had asthma,
raised specific IgE or an eosinophilia, only 25% had true markers to show they were atopic (59). Finally, Emanuel et al. (60)
found relatively lower percentages of allergic patients in the
group of patients with the most severe sinus disease on CT
scan and Iwens et al. (61) reported that the prevalence and extent
of sinus mucosa involvement on CT was not determined by
the atopic state.
Also in animal experiments it was shown that shortly after

exposure to pathogenic bacteria, like Streptococcus pneumoniae,
Hemophilus influenzae, Pseudomonas aeruginosa, a significant
loss of ciliated cells from sinus mucosa and a corresponding
disruption of normal mucociliary flow occurred (53).
4-3-3 Allergy
Review articles on sinusitis have suggested that atopy predisposes to rhinosinusitis (54). This theory is attractive given the
popularity of the concept that disease in the ostiomeatal area
contributes to the development of sinus disease. Mucosa in an
individual with allergic rhinitis might be expected to be
swollen and therefore more liable to obstruct sinus ostia,
reduce ventilation, leading to mucus retention which in turn
might be more prone to infection. Furthermore there has been
an increase in the body of opinion that regard the mucosa of
the nasal airway as being in a continuum with the paranasal
sinuses reflected in the term rhinosinusitis (55). However, the
number of studies determining the occurrence of ARS in
patients with and without allergy are very limited.
Savolainen studied the occurrence of allergy in 224 patients
with verified ARS by means of an allergy questionnaire, skin
testing, and nasal smears. Allergy was found in 25% of the
patients and considered probable in another 6.5%. The corresponding percentages in the control group were 16.5 and 3,
respectively. There were no differences between allergic and
non-allergic patients in the number of previous ARS episodes
nor of previously performed sinus irrigations. Bacteriological
and radiological findings did not differ significantly between
the groups (56). Alho showed that subjects with allergic IgEmediated rhinitis had more severe paranasal sinus changes on
CT scanning than non-allergic subjects during viral colds.
These changes indicate impaired sinus functioning and may
increase the risk of bacterial sinusitis (57). Alho studied cellular
modifications during acute viral rhinitis in three different
groups (allergic, recurrent sinusitis, and healthy patients). No
significant difference in inflammatory cells was found in any
group during acute (D0) and convalescent (D21) phases.
In a small prospective study, no difference in prevalence of
purulent rhinosinusitis was found between patients with and
without allergic rhinitis (58). Furthermore, allergy was found in
31.5% of patients with verified acute maxillary sinusitis and
there were no differences between allergic and non-allergic
patients in the number of prior ARS episodes (56). Newman et
Radiologic studies are unhelpful in unravelling the correlation

between allergy and rhinosinusitis. High percentages of sinus
mucosa abnormalities are found on radiologic images of allergic patients, e.g. 60% incidence of abnormalities on CT scans
among subjects with ragweed allergy during the season (62).
However, one should interpret this data with caution in view
of the fact that high percentages of incidental findings are
found on radiologic images of the sinus mucosa in individuals
without nasal complaints, ranging from 24.7 % to 49.2 % (63-66),
that the normal nasal cycle induces cyclical changes in the
nasal mucosa volume (67), and that radiological abnormalities do
not correlate well with patient's symptoms (62).
Holzmann reported an increased prevalence of allergic rhinitis
in children with orbital complications of ARS, and these complications occurred especially during the pollen season (68). In a
study involving 8723 children, Chen and colleagues found the
prevalence of sinusitis to be significantly higher in children
with allergic rhinitis than in children without allergies (69).
In conclusion, although an attractive hypothesis, we can repeat
the statement made a decade ago that there are no published
prospective reports on the incidence of infective rhinosinusitis
in populations with and without clearly defined allergic rhinosinusitis (70).
4-3-4 Helicobacter pylori and laryngopharyngeal reflux
Very few articles can be found in the literature regarding the
role of the laryngopharyngeal reflux (LPR) and/or
Helicobacter pylori infection in the pathogenesis of ARS. More
have investigated a possible role in CRS but without significant
results. Wise described a correlation between LPR (detected
either with pH sensor and/or with symptom scores), and postnasal drip without the typical findings of CRS, a problem
which might predispose a subject to an acute bacterial infection (71). In a case report, Dinis underlines the presence of
Helicobacter in the sphenoid sinus of a patient with severe
sphenoid sinusitis that was also treated with Helicobacter
pylori therapy (72). Therefore, even if there is no clear correlation between reflux disease and/or Helicobacter pylori infection and ARS, this is undoubtedly a field for future investigation when one considers the increase of this gastrointestinal
problem in developed countries and the fact that the acid content of reflux and the Helicobacter infection itself can cause
mucociliary impairment.
12
4-3-5 Other risk factors : ventilation, naso-gastric tube

Nosocomial sinusitis are frequently observed in intensive care
(73, 74)
and have been generally linked to naso-tracheal intubation
(75)
or presence of naso-gastric tube (76). The maxillary sinus is
frequently involved. Endoscopy of the middle meatus is useful
to determine the presence of purulence in the middle meatus
and if the culture is possible. Bacteriology differs from community acquired cases with a more frequent isolation of anaerobic bacteria (77). Treatment may include, complementary to
adjustment of antibiotic treatment, drainage, daily lavage and
removal of the grastic tube (78).
4-4 Chronic rhinosinusitis (CRS) without nasal polyps
Supplement 20
which may be considered representative of the general population in Belgium, Gordts et al. (87) reported that 6% of subjects
suffered from chronic nasal discharge. A comparative study in
the north of Scotland and the Caribbean found that in ORL
clinics in both populations there was a similar prevalence of
CRS (9.6% and 9.3% respectively) (88). Not withstanding the
shortcomings of epidemiologic studies on CRS, it represents a
common disorder of multifactorial origin. A list of factors will
be discussed in the following chapter which are believed to be
etiologically linked to CRS.
4-5 Factors associated with chronic rhinosinusitis (CRS) without
nasal polyps
The paucity of accurate epidemiologic data on CRS with or

without nasal polyps contrasts with the more abundant information on microbiology, diagnosis and treatment options for
these conditions. When reviewing the current literature on
CRS, it becomes clear that giving an accurate estimate of the
prevalence of CRS remains speculative, because of the heterogeneity of the disorder and the diagnostic imprecision often
used in publications. In a survey on the prevalence of chronic
conditions, it was estimated that CRS, defined as having sinus
trouble for more than 3 months in the year before the interview, affects 15.5% of the total population in the United States
(79)
, ranking this condition second in prevalence among all
chronic conditions. Subsequently the high prevalence of CRS
was confirmed by another survey suggesting that 16% of the
adult US population has CRS (80). However, the prevalence of
doctor-diagnosed CRS is much lower; a prevalence of 2% was
found using ICD-9 codes as an identifier (81). Corroboration of
the definitive diagnosis of CRS should be done with nasal
endoscopy (82) or CT (83). As the diagnosis of CRS has primarily
been based on symptoms, often excluding dysosmia, this
means that the diagnosis of CRS is often overestimated (83). The
majority of primary care physicians do not have the training or
equipment to perform nasal endoscopy that also leads to overdiagnosis (84).
4-5-1 Ciliary impairment

As may be concluded from the section on anatomy and pathophysiology, ciliary function plays an important role in the clearance of the sinuses and the prevention of chronic inflammation. Secondary ciliary dyskinesia is found in patients with
chronic rhinosinusitis, and is probably reversible, although
restoration takes some time (89) As expected in patients with
Kartageners syndrome and primary ciliary dyskinesia, CRS is a
common problem and these patients usually have a long history of respiratory infections. In patients with cystic fibrosis (CF),
the inability of the cilia to transport the viscous mucus causes
ciliary malfunction and consequently CRS. Nasal polyps are
present in about 40% of patients with CF (90). These polyps are
generally more neutrophilic than eosinophilic in nature but
may respond to steroids nonetheless, as inhaled steroids in
patients with CF reduce neutrophilic inflammation (91-93).
Interestingly, the prevalence rate of CRS was substantially

higher in females with a female/male ratio of 6/4 (79). In
Canada, the prevalence of CRS, defined as an affirmative
answer to the question Has the patient had sinusitis diagnosed
by a health professional lasting for more than 6 months?
ranged from 3.4% in male to 5.7% in female subjects (85). The
prevalence increased with age, with a mean of 2.7% and 6.6%
in the age groups of 20-29 and 50 59 years, respectively. After
the age of 60 years, prevalence levels of CRS levelled off to
4.7% (85). In a nationwide survey in Korea, the overall prevalence of CRS, defined as the presence of at least 3 nasal symptoms lasting more than 3 months together with the endoscopic
finding of nasal polyps and/or mucopurulent discharge within
the middle meatus, was 1.01% (86), with no differences between
age groups or gender. By screening a non-ENT population,
It has been postulated (97) that swelling of the nasal mucosa in

allergic rhinitis at the site of the sinus ostia may compromise
ventilation and even obstruct sinus ostia, leading to mucus
retention and infection. Futhermore, there has been an
increase in the body of opinion that regard the mucosa of the
nasal airway as being in a continuum with the paranasal sinuses and hence the term rhinosinusitis was introduced (55).
However, critical analysis of the papers linking atopy as a risk
factor to infective rhinosinusitis (chronic or acute) reveal that
whilst many of the studies suggest a higher prevalence of allergy in patients presenting with symptoms consistent with sinusitis than would be expected in the general population, there
may well have been a significant selection process, because the
doctors involved often had an interest in allergy (30, 98-102). A number of studies report that markers of atopy are more prevalent
4-5-2 Allergy
Review articles on rhinosinusitis have suggested that atopy
predisposes to its development (54, 94). It is tempting to speculate
that allergic inflammation in the nose predisposes the atopic
individual to the development of CRS. Both conditions share
the same trend of increasing prevalence (95, 96) and are frequently
associated.
13
in populations with CRS. Benninger reported that 54% of outpatients with CRS had positive skin prick tests (103). Among
CRS patients undergoing sinus surgery, the prevalence of positive skin prick tests ranges from 50% to 84% (56, 60, 104), of which
the majority (60%) have multiple sensitivities (60). As far back as
1975, Friedman reported an incidence of atopy in 94% of
patients undergoing sphenoethmoidectomies (105).
However, the role of allergy in CRS is questioned by other epidemiologic studies showing no increase in the incidence of
infectious rhinosinusitis during the pollen season in pollensensitized patients (70). Taken together, epidemiologic data
show an increased prevalence of allergic rhinitis in patients
with CRS, but the role of allergy in CRS remains unclear.
Notwithstanding the lack of hard epidemiologic evidence for a
clear causal relationship between allergy and CRS, it is clear
that failure to address allergy as a contributing factor to CRS
diminishes the probability of success of a surgical intervention
(106)
. Among allergy patients undergoing immunotherapy, those
who felt most helped by immunotherapy were the subjects
with a history of recurrent rhinosinusitis, and about half of the
patients, who had had sinus surgery before, believed that the
surgery alone was not sufficient to completely resolve the
recurrent episodes of infection (106).
atric CRS section (see Chapter 7-6). However, dysfunction of

the immune system may occur later in life and present with
CRS. In a retrospective review of refractory sinusitis patients,
Chee et al. found an unexpectedly high incidence of immune
dysfunction (114). Of the 60 patients with in vitro T-lymphocyte
function testing, 55% showed abnormal proliferation in
response to recall antigens. Low immunoglobulin G, A, and M
titres were found in 18%, 17%, and 5%, respectively, of patients
with refractory sinusitis. Common variable immunodeficiency
was diagnosed in 10% and selective IgA deficiency in 6% of
patients. Therefore, immunological testing should be an integral part of the diagnostic pathway of patients with CRS. In a
cross-sectional study to assess the overall prevalence of otolaryngologic diseases in patients with HIV infection, Porter et
al. (115) reported that sinusitis was present in more than half of
the HIV-positive population, ranking this condition one of the
most prevalent diseases in HIV-positive individuals. However,
the relevance of these data is questioned as there was no difference in sinonasal symptom severity between HIV-positive
and AIDS patients nor was there a correlation between CD4+
cell counts and symptom severity. In a more detailed study,
Garcia-Rodrigues et al. (116) reported a lower incidence of rhinosinusitis (34%), but with a good correlation between low
CD4+ cell count and the probability of rhinosinusitis. It
should also be mentioned here that atypical organisms like
Aspergillus spp, Pseudomonas aeruginosa and microsporidia are
often isolated from affected sinuses and that neoplasms such
as non-Hodgkin lymphoma and Kaposis sarcoma, may
account for sinonasal problems in patients with AIDS (117).
4-5-3 Asthma
Recent evidence suggests that allergic inflammation in the
upper and lower airways coexist and should be seen as a continuum of inflammation, with inflammation in one part of the
airway influencing its counterpart at a distance. The arguments
and consequences of this statement are summerized in the
ARIA document (107). Rhinosinusitis and asthma are also frequently associated in the same patients, but their inter-relationship is poorly understood. The evidence that treatment of
rhinosinusitis improves asthma symptoms and hence reduces
the need for medication to control asthma, mainly results from
research in children and will be discussed below (Chapter 9-7).
In short, improvements in both asthma symptoms and medication have been obtained after surgery for rhinosinusitis in children with both conditions (108-110).
Studies on radiographic abnormalities of the sinuses in asthmatic patients have shown a high prevalence of abnormal sinus
mucosa (111, 112). All patients with steroid-dependant asthma had
abnormal mucosal changes on CT compared to 88% with mild
to moderate asthma (113). Again caution should be exercised in
the interpretation of these studies. Radiographically detected
sinus abnormalities in sensitized patients may reflect inflammation related to the allergic state rather than to sinus infection.
4-5-4 Immunocompromised state
Among conditions associated with dysfunction of the immune
system, congenital immunodeficiencies manifest themselves
with symptoms early in life and will be dealt with in the paedi-
4-5-5 Genetic factors

Although chronic sinus disease has been observed in family
members, no genetic abnormality has been identified linked to
CRS. However, the role of genetic factors in CRS has been
implicated in patients with cystic fibrosis (CF) and primary ciliary dyskinesia (Kartagener's syndrome). CF is one of the most
frequent autosomal recessive disorders of the Caucasian population, caused by mutations of the CFTR gene on chromosome 7 (118). The most common mutation, F508, is found in 70
to 80% of all CFTR genes in Northern Europe (119, 120). Upper airway manifestations of CF patients include chronic rhinosinusitis and nasal polyps, which are found in 25 to 40 % of CF
patients above the age of 5 (121-124). Interestingly, Jorissen et al.
(125)
reported that F508 homozygosity represents a risk factor
for paranasal sinus disease in CF and Wang reported that
mutations in the gene responsible for CF may be associated
with the development of CRS in the general population (126).
4-5-6 Pregnancy and endocrine state
During pregnancy, nasal congestion occurs in approximately
one-fifth of women (127). The pathogenesis of this disorder
remains unexplained, but there have been a number of proposed theories. Besides direct hormonal effects of oestrogen,
progesterone and placental growth hormone on the nasal
14
mucosa, indirect hormonal effects like vascular changes may

be involved. Whether pregnancy rhinitis predisposes to the
development of sinusitis, is not clear. In a small prospective
study, Sobol et al. (128) report that 61% of pregnant women had
nasal congestion during the first trimester, whereas only 3%
had sinusitis. In this study, a similar percentage of non-pregnant women in the control group developed sinusitis during
the period of the study. Also in an earlier report, the incidence
of sinusitis in pregnancy was shown to be quite low, i.e. 1.5%
(129)
. In addition, thyroid dysfunction has been implicated in
CRS, b there is only limited data on the prevalence of CRS in
patients with hypothyroidism.
4-5-7 Local host factors
Certain anatomic variations such as concha bullosa, nasal septal deviation and a displaced uncinate process, have been suggested as potential risk factors for developing CRS (130) .
However, some studies that have made this assertion have
equated mucosal thickening on CT with CRS (131) when it has
been shown that incidental mucosal thickening occurs in
approximately a third of an asymptomatic population (20).
However, Bolger et al. (132) found no correlation between CRS
and bony anatomic variations in the nose. Holbrook et al. also
found no correlation between sinus opacification, anatomical
variations and symptom scores (133). However, one should mention here that no study has so far investigated whether a particular anatomic variation can impair drainage of the ostiomeatal
complex per se. Whilst some authors have postulated that
anatomical variations of the paranasal sinuses can contribute to
ostial obstruction (134) there are several studies that show the
prevalence of anatomical variations is no more common in
patients with rhinosinusitis or polyposis than in a control population (20, 21, 135). One area where conjecture remains is the effect
of a deviated septum. There are a number of studies that show
no correlation between septal deviation and the prevalence of
CRS. (136, 137). Whilst there is no recognised method of objectively defining the extent of a deviated septum, some studies have
found a deviation of more than 3mm from the midline to be
more prevalent in rhinosinusitis (138, 139) whilst others have not (21,
137, 140)
. Taken together, there is no evidence for a causal correlation between nasal anatomic variations in general and the incidence of CRS. In spite of the observation that sinonasal complaints often resolve after surgery, this does not necessarily
imply that anatomic variation is etiologically involved.
CRS of dental origin should not be overlooked when considering the etiology of CRS. Obtaining accurate epidemiologic data
on the incidence of CRS of dental origin is not possible as the
literature is limited to anecdotal reports.
Supplement 20
4-5-8 Micro-organisms
4-5-8-1 Bacteria
Although it is often hypothesized that CRS evolves from ARS,
this has never been proven. Furthermore, the role of bacteria
in CRS is far from clear. A number of authors have described
the microbiology of the middle meatus and sinuses. However
if and which of these pathogen are contributory to the disease
remains a matter of debate. Bhattacharyya (2005) found that
both anaerobes and aerobic species could be recovered from
both diseased and the non-diseased contralateral side of
patients with chronic rhinosinusitis casting doubt on the aetiologic role of bacteria in CRS (141). Anaerobes are more prevalent
in infections secondary to dental problems.
Arouja isolated aerobes from 86% of the middle meatus samples
of CRS patients, whereas anaerobes were isolated in 8%. The
most frequent microorganisms were Staphylococcus aureus
(36%), coagulase-negative Staphylococcus (20%), and Streptococcus
pneumoniae (17%). Middle meatus and maxillary sinus cultures
presented the same pathogens in 80% of cases. In healthy individuals, coagulase-negative Staphylococcus (56%), S. aureus (39%),
and S. pneumoniae (9%) were the most frequent isolates. (142).
Some authors suggest that as chronicity develops, the aerobic
and facultative species are gradually replaced by anaerobes (143, 144).
This change may result from the selective pressure of antimicrobial agents that enable resistant organisms to survive and from
the development of conditions appropriate for anaerobic growth,
which include the reduction in oxygen tension and an increase
in acidity within the sinus. Often polymicrobial colonisation is
found; the contribution to the disease of the different pathogens
remains unclear. The presence of intracellular
S. aureus in epithelial cells of the nasal mucosa has been suggested to pay a significant risk factor for recurrent episodes of
rhinosinusitis due to persistent bacterial clonotypes, which
appear refractory to antimicrobial and surgical therapy (145).
4-5-8-2 Fungi
Fungi have been cultured from human sinuses (146). Their presence may be relatively benign, colonizing normal sinuses or
forming saprophytic crusts. They may also cause a range of
pathology, ranging from non-invasive fungus balls to invasive,
debilitating disease (147).
There is an increasing interest in the concept that the most
common form of sinus disease induced by fungus may be
caused by the inflammation stimulated by airborne fungal antigens. In 1999 it was proposed that most patients with CRS
exhibit eosinophilic infiltration and the presence of fungi by
histology or culture (148). This assertion was based on finding
positive fungal culture by using a new culture technique in 202
of 210 (96%) patients with CRS who prospectively were evaluated in a cohort study. No increase in type I sensitivity was found
in patients as compared with controls. The term eosinophilic
15
chronic rhinosinusitis was proposed to replace previously used

nomenclature (allergic chronic rhinosinusitis). Using this new
culture technique, the same percentage of positive fungi cultures was also found in normal controls (149).
4-5-10 Environmental factors

Cigarette smoking was associated with a higher prevalence of
rhinosinusitis in Canada (85), whereas this observation was not
confirmed in a nationwide survey in Korea (86). Other
lifestyle-related factors are undoubtedly involved in the chronic inflammatory processes of rhinosinusitis. For instance, low
income was associated with a higher prevalence of CRS (85).
In spite of in vitro data on the toxicity of pollutants on respiratory epithelium, there exists no convincing evidence for the
etiologic role of pollutants and toxins such as ozone in CRS.
Pant et al. suggest that fungal-specific immunity is characterised by serum IgG3 and not IgE distinguished patients with
CRS and eosinophilic mucus from healthy controls, regardless
of whether fungi were found within the mucus. They found no
differences between those with CRS and the eosinophilic
mucus group and a group with allergic fungal rhinosinusitis (150).
Some authors suggest that non IgE mediated mechanisms to
fungal spores might be responsible for eosinophilic inflammation seen in some individuals (151) Shin et al. found that patients
with CRS had an exaggerated humoral and TH1 and TH2 cellular response to common airborne fungi, particularly
Alternaria. No increase in type I sensitivity was found in
patients as compared with controls (152). In another study no
correlation was found between fungal parameters and the clinical parameters of CRS or the presence of eosinophilia (153) and
the use of quantitative PCR produced a recovery rate of fungi
of 46% in a group with CRS and a control group (154).
A broad array of fungi has been identified in the sinus cavities
of patients with sinusitis through varied staining and culture
techniques (148, 149). As with the isolation of bacteria in sinus cavities in these patients, the presence of fungi does not prove that
these pathogens directly create or perpetuate disease. The use
of topical or systemic antifungal agents have not consistently
been shown to help patients with CRS (155, 156).
4-5-9 Osteitisthe role of bone
Areas of increased bone density and irregular bony thickening
are frequently seen on CT in areas of chronic inflammation
and may be a marker of the chronic inflammatory process (157).
However, the effect during the initial phases of a severe CRS
frequently appears as rarefaction of the bony ethmoid partitions. Although to date bacterial organisms have not been
identified in the bone in either humans or animal models of
CRS, it has been suggested that that this irregular bony thickening is a sign of inflammation of the bone which in turn
might maintain mucosal inflammation (158).
In rabbit studies it was demonstrated that not only the bone
adjacent to the involved maxillary sinus become involved, but
that the inflammation typically spreads through the Haversian
canals and may result in bone changes consistent with some
degree of chronic osteomyelitis at a distance from the primary
infection (159, 160) It is certainly possible that these changes, if further confirmed in patients, may at least in part, explain why
CRS is relatively resistant to therapy.
4-5-11 Iatrogenic factors

Among risk factors of CRS, iatrogenic factors should not be
forgotten as they may be responsible for the failure of sinus
surgery. The increasing number of sinus mucocoeles seems to
correlate with the increase in endoscopic sinus surgery procedures. Among a group of 42 patients with mucocoeles, 11 had
prior surgery within 2 years prior to presentation (161). Another
reason for failure after surgery can be the recirculation of
mucus out of the natural maxillary ostium and back through a
separate surgically created antrostomy resulting in an increased
risk of persistent sinus infection (162).
4-5-12 Helicobacter pylori and laryngopharyngeal reflux
Heliobacter pylori DNA has been detected in between 11% (163)
and 33% (164) of sinus samples from patients with CRS but not
from controls. However, as in ARS this does not prove a
causal relationship.
4-6 Chronic rhinosinusitis with nasal polyps
Epidemiologic studies rely on nasal endoscopy and/or questionnaires to report on the prevalence of nasal polyps (NP).
Large NP can be visualized by anterior rhinoscopy, whereas
nasal endoscopy is warranted for the diagnosis of smaller NP.
Nasal endoscopy appears to be a prerequisite for an accurate
estimate of the prevalence of NP, as not all patients that claim
to have NP actually have polyps on nasal endoscopy (165).
Therefore, surveys based on questionnaires asking for the presence of NP, may provide us with an overestimation of the selfreported prevalence of NP. Recently, a French expert panel of
ENT specialists elaborated a diagnostic questionnaire/algorithm with 90 % sensitivity and specificity (166).
In the light of epidemiologic research, a distinction needs to be
made between clinically silent NP or preclinical cases, and
symptomatic NP. Asymptomatic polyps may transiently be present or persist, and hence remain undiagnosed until they are
discovered by clinical examination. On the other hand, polyps
that become symptomatic may remain undiagnosed, either
because they are missed during anterior rhinoscopy and/or
because patients do not see their doctor for this problem.
Indeed, one third of patients with CRS with NP do not seek
medical advice for their sinonasal symptoms (167). Compared to
16
patients with CRS with NP not seeking medical attention,

those actively seeking medical care for CRS with NP had more
extensive NP with more reduction of peak nasal inspiratory
flow and greater impairment of the sense of smell (168).
In a population-based study in Skvde, Sweden, Johansson et al.
reported a prevalence of nasal polyps of 2.7% of the total population. In this study, NP were diagnosed by nasal endoscopy
and were more frequent in men (2.2 to 1), the elderly (5% at 60
years of age and older) and asthmatics. In a nationwide survey
in Korea, the overall prevalence of polyps diagnosed by nasal
endoscopy was 0.5% of the total population (136). Based on a
postal questionnaire survey in Finland, Hedman et al. (32)
found that 4.3% of the adult population answered positively to
the question as to whether polyps had been found in their nose.
Using a disease-specific questionnaire, Klossek et al. (167) report a
prevalence of NP of 2.1% in France.
(165)
From autopsy studies, a prevalence of 2% has been found

using anterior rhinoscopy (169). After removing whole naso-ethmoidal blocks, nasal polyps were found in 5 of 19 cadavers (170),
and in 42% of 31 autopsy samples combining endoscopy with
endoscopic sinus surgery (171). The median age of the cases in
the 3 autopsy studies by Larsen and Tos ranged from 70 to 79
years. From these cadaver studies, one may conclude that a
significant number of patients with NP do not feel the need to
seek medical attention or that the diagnosis of NP is often
missed by doctors.
It has been stated that between 0.2% and 1% of people develop
NP at some stage (172). In a prospective study on the incidence of
symptomatic NP, Larsen and Tos (173) found an estimated incidence of 0.86 and 0.39 patients per thousand per year for males
and females, respectively. The incidence increased with age,
reaching peaks of 1.68 and 0.82 patients per thousand per year
for males and females respectively in the age group of 50-59
years. When reviewing data from patient records of nearly 5,000
patients from hospitals and allergy clinics in the US in 1977, the
prevalence of NP was found to be 4.2% (174), with a higher prevalence (6.7%) in the asthmatic patients.
In general, NP occur in all races and becomes more common
with age (167, 175-178). The average age of onset is approximately 42
years, which is 7 years older than the average age of the onset
of asthma (179-181). NP are uncommon under the age of 20 (182) and
are more frequently found in men than in women (32, 173, 183),
except in the studies by Settipane (174) and Klossek (167).
4-7 Factors associated with chronic rhinosinusitis with nasal polyps
4-7-1 Allergy
From 0.5 to 4.5% of subjects with allergic rhinitis have NP (34, 35,
184),
which compares with the normal population (172). In children
the prevalence of CRS with NP has been reported to be 0.1%
(34) and Kern found NP in 25.6% of patients with allergy com-
Supplement 20
pared to 3.9% in a control population (185). On the other hand,

the prevalence of allergy in patients with NP has been reported
as varying from 10% (186), to 54% (187) and 64% (188). Contrary to
reports that have implicated atopy as being more prevalent in
patients with NP, others have failed to show this (34, 184, 189-191).
Recently, Bachert at al. (192) found an association between levels
of both total and specific IgE and eosinophilic infiltration in
NP. These findings were unrelated to skin prick test results.
Although intradermal test to food allergens are known to be
unreliable,, positive intradermal tests to food allergens have
been reported in 70 % (193) and 81% (194) of NP patients compared
to respectively 34% and 11% of controls. Based on questionnaires, food allergy was reported by 22% (167) and 31% (177) of
patients with NP, which was significantly higher than in nonNP controls (167) Pang et al. found a higher prevalence of positive intradermal food tests (81%) in patients with NP compared
to 11% in a small control group (194). Further research is needed
to investigate a possible role for food allergy in the initiation
and perpetuation of NP.
4-7-2 Asthma
Bronchial symptoms are associated with NP in a subgroup of
patients (195). Wheezing and respiratory discomfort are present
in 31% and 42% of patients with NP, and asthma is reported by
26% of patients with NP, compared to 6% of controls (167).
Alternatively, 7% of asthmatic patients have NP (34), with a
prevalence of 13% in non-atopic asthma (skin prick test and
total and specific IgE negative) and 5% in atopic asthma (182).
Late onset asthma is associated with the development of nasal
polyps in 10-15% (34). Asthma develops first in approximately
69% of patients with both asthma and CRS with NP. NP take
between 9 and 13 years to develop, only two years in aspirin
induced asthma (196) Ten percent develop both polyps and asthma simultaneously and the remainder develop polyps first and
asthma later (between 2 and 12 years) (175). Generally NP are
twice as prevalent in men although the proportion of those
with polyps and asthma is twice that in women than men.
Women that have nasal polyps are 1.6 times more likely to be
asthmatic and 2.7 times to have allergic rhinitis (178).
4-7-3 Aspirin sensitivity
In patients with aspirin sensitivity 36-96% have CRS with NP (35,
182, 197-202)
and up to 96% have radiographic changes affecting their
paranasal sinuses (203). Patients with aspirin sensitivity, asthma
and NP are usually non-atopic and the prevalence increases over
the age of 40 years. The children of patients with asthma, NP,
and aspirin sensitivity had NP and rhinosinusitis more often
than the children of controls (204). Concerning hereditary factors,
HLA A1/B8 has been reported as having a higher incidence in
patients with asthma and aspirin sensitivity (205) although Klossek
et al (167) found no difference between gender in 10,033 patients.
Zhang found that IgE antibodies to enterotoxins can be found
in the majority of patients polyps who are aspirin sensitive (206).
4-7-4 Genetics predisposition of chronic rhinosinusitis with nasal
17
polyps
Although the mechanisms involved in the pathogenesis of
nasal polyps (NP) remain largely unclear, there are reports suggesting an underlying genetic predisposition. This concept is
supported by some clinical data and genetic studies. This chapter does not include NP in cystic fibrosis (CF), which is known
to be a hereditary disease with multi-systemic involvement
with genetic variations, presenting with defect in chloride
transport across membranes and dehydrated secretions.
found to be associated with NP, such susceptibility can be

influenced by ethnicity. In the Mexican Mestizo population,
increased frequency of the HLA-DRB1*03 allele and of the
HLA-DRB1*04 allele were found in patients with NP as compared to healthy controls (215).
4-7-4-1 Family and twin studies

An interesting observation is that NP are frequently found to
run in families, suggesting a hereditary or with shared environmental factor. In the study by Rugina et al. (177), more than half
of 224 NP patients (52%) had a positive family history of NP.
The presence of NP was considered when NP had been diagnosed by an ENT practitioner or the tients had undergone
sinus surgery for NP. A lower percentage (14%) of familial
occurrence of NP was reported earlier by Greisner et al. (86) in
smaller group (n = 50) of adult patients with NP. Thus, these
results strongly suggest the existence of a hereditary factor in
the pathogenesis of NP.
However, studies of monozygotic twins have not shown that
both siblings always develop polyps, indicating that environmental factors are likely to influence the occurrence of NP (207,
208)
. NPs have been described in identical twins, but given the
prevalence of nasal polyps it might be expected that there
would be more than a rare report of this finding (209).
4-7-4-2 Linkage analysis and association studies
In the literature, some studies were able to show linkage of
certain phenotypes of NP to candidate gene polymorphisms.
Karjalainen et al. reported that subjects with a single G-to-T
polymorphism in exon 5 at +4845 of the gene encoding IL1alpha (IL-1A) were found to have less risk of developing NP
as compared to subjects with common G/G genotype (210). In
another study, polymorphism of IL-4 (IL-4/-590 C-T), a potential determinant of IgE mediated allergic disease, was found to
be associated with a protective mechanism against NPs in the
Korean populations (211).
A number of genetic association studies found a significant
correlation between certain HLA (human leukocyte antigen)
alleles and NP. HLA is the general name of a group of genes in
the human major histocompatibility complex (MHC) region
on the human chromosome 6 that encodes the cell-surface
antigen-presenting proteins. Luxenberger et al. (212) reported an
association between HLA-A74 and NPs, whereas MolnarGabor et al. (213) reported that subjects carrying HLA-DR7DQA1*0201 and HLA-DR7-DQB1*0202 haplotype had a 2 to 3
times odds ratio of developing NP. The risk of developing NP
can be as high as 5.53 times in subjects with HLA-DQA1*0201DQB1*0201 haplotype (214). Although several HLA alleles were
4-7-4-3 Multiple gene expressions in nasal polyps

The development and persistence of mucosal inflammation in
NPs have been reported to be associated with numerous genes
and potential single nucleotide polymorphisms (SNPs). The
products of these genes determine various disease processes,
such as immune modulation or immuno-pathogenesis, inflammatory cells (e.g., lymphocytes, eosinophils, neutrophils) development, activation, migration and life span, adhesion molecule
expression, cytokine synthesis, cell-surface receptor display, and
processes governing fibrosis and epithelial remodelling.
In the literature, gene expression profiles in nasal polyp have
been performed by many studies, including the major repertoire of disease-related susceptibility genes or genotypic markers (Table 4-1). With the advance of microassay technique,
expression profiles of over 10,000 of known and novel genes
can be detected. A recent study showed that in NP tissues, 192
genes were upregulated by at least 2-fold, and 156 genes were
downregulated by at least 50% in NP tissues as compared to
sphenoid sinuses mucosa (216). In another study (217), microarray
analysis was used to investigate the expression profile of 491
immune-associated genes in nasal polyps. The results showed
that 87 genes were differentially expressed in the immuneassociated gene profile of nasal polyps, and 15 genes showed
differential expression in both NP and controls (turbinate).
These seemingly conflicting results are likely due to the heterogeneity of inflammatory cells within nasal polyps and the
differences in study designs and analytic approaches. In addition, in most of the published studies, the functional significance of aberrant gene expression with respective to the pathogenesis of NP is yet to be determined.
The expression of gene products is regulated at multiple levels,
such as during transcription, mRNA processing, translation,
phosphorylation and degradation. Although some studies were
able to show certain NP associated polymorphisms and genotypes, the present data is still fragmented. Same as for many
common human diseases, inherited genetic variation appears
to be critical but yet still largely unexplained. Future studies
are needed to identify the key genes underlying the development or formation of NP and to investigate the interactions
between genetic and environmental factors that influence the
complex traits of this disease. Identifying the causal genes and
variants in NP is important in the path towards improved prevention, diagnosis and treatment of NPs.
4-7-5 Environmental factors
18
Supplement 20
The role of environmental factors in the development of CRS

with NP is unclear. No difference in the prevalence of CRS
with NP has been found related to the patient's habitat or pollution at work (177). One study found that a significantly smaller
proportion of the population with polyps were smokers compared to an unselected population (15% vs. 35%) (177), whereas
this was not confirmed by others (167). One study reports on the
association between the use of a woodstove as a primary
source of heating and the development of NP (218).
4-8 Epidemiology and predisposing factors for rhinosinusitis in
children
4-8-1 Epidemiology
Few prospective population studies exist (see Table 4.1). The
first longitudinal study was performed by Maresh and
Washburn (219) who followed 100 healthy children from birth to
maturity, looking at history, physical examination and routine
postero-anterior radiograph of the paranasal sinuses 4 times a
year. Postero-anterior standard X-ray of the sinuses in a child
gives only information about the maxillary sinuses. There existed a relatively constant percentage (30 %) of "pathologic" antra
in the films taken between 1 and 6 years of age. From 6 to 12
years, this percentage dropped steadily to approximately 15%.
Variations in size of the sinuses occurred frequently, without
any relation to infections. When there was an upper respiratory
tract infection ("URTI") in the previous 2 weeks, less than 50%
showed clear sinuses. Tonsillectomy had no demonstrable
effect on the radiographic appearance of the sinuses.
Since the introduction of CT scanning, it has become clear
that a runny nose in a child is not only due to limited rhinitis
or adenoid hypertrophy, but that in the majority of the cases
the sinuses are involved as well 64% in a CT scan study of
children with a history of chronic purulent rhinorrhea and
nasal obstruction (220). In an MRI study of a non-ENT paediatric
population (87) it was shown that the overall prevalence of
sinusitis signs in children was 45%. This prevalence increased
in the presence of a history of nasal obstruction to 50%, to 80%
when bilateral mucosal swelling was present on rhinoscopy, to
81% after a recent upper respiratory tract infection (URI), and
to 100% in the presence of purulent secretions. Kristo et al
found a similar overall percentage (50 %) of abnormalities on
MRI in 24 school children (221). At follow-up after 6 to 7 months

about half of the abnormal sinuses on MRI findings had
resolved or improved without any intervention.
Therefore, in younger children with CRS, there exists a spontaneous tendency towards recovery after the age of 6 to 8 years. A
decrease in prevalence of rhinosinusitis in older children was
also confirmed by other authors in patient populations (223).
4-8-2 Predisposing factors
These include day care (224, 225), nasal obstruction and passive
smoking (226-228)). No protective effect of breast- feeding has been
demonstrated (229, 230). Urban atmospheric pollution in Sao Paulo
was associated with a higher prevalence of rhinitis, sinusitis and
URTIs in 1000 schoolchildren aged 7-14 years than that seen in
1000 rural children (231). Children with tonsillitis or otitis media
are more likely to suffer from sinusitis than those without suggesting that immunological deficiencies are involved (232). CRS is
more common in children with mucociliary dysfunction due to
CF (often plus NP) or primary ciliary dyskinesia and in those
with humoral immune deficiencies (233). Heterozygotes for CF
genes occur more commonly than expected in the CRS population suggesting that this may be a predisposing factor (234).
Anatomical variations of the lateral nasal wall are common in
children but bear no relationship to sinusitis (235).
4-9 Conclusion
The overview of the currently available literature illustrates the
paucity of accurate information on the epidemiology of ARS,
and CRS with and without NP, especially in European countries, and highlights the need for large-scale epidemiologic
research exploring their prevalence and incidence. Only by the
use of well standardized definitions for ARS, CRS and NP, and
well-defined inclusion criteria for epidemiologic research, will it
be possible to obtain accurate epidemiologic data on the natural
evolution of CRS and NP, the influence of ethnic background
and genetic factors on CRS and NP, and the factors associated
with the disease manifestation. Such studies need to be performed in order to make significant progress in the development
of diagnostic and therapeutic strategies for affected patients.
Table 4-1. Results of epidemiologic studies in rhinosinusitis is children.

author/year
Maresh, Washburn 1940
(219)
Bagatsch 1980 (222)
included group
100 healthy children
from birth to maturity
24,000 children in the

area of Rostock
followed up for 1 year
examination method
ENT-examination
and pa-Xray of sinuses
result
30% pathologic antra overall
>50% pathologic antra with
previous upper airway infection
(URTI) in the last two weeks
one or more URTI in
the year:
0-2 years: 84%
4-6 years: 74%
> 7 years: 80%
conclusion
high rate of pathology, can be
under or over estimated because
of the examination technique
increased between
November and February
19
5. Inflammatory mechanisms in acute and chronic rhinosinusitis

with or without nasal polyposis
5-1 Introduction
Rhinosinusitis is a heterogeneous group of diseases, with different underlying aetiologies and pathomechanisms, and may
indeed represent an umbrella, covering different disease entities. It is currently not understood whether acute recurrent rhinosinusitis necessarily develops into chronic rhinosinusitis,
which then possibly gives rise to polyp growth, or whether
these entities develop independently from each other. All of
these items may be referred to as rhinosinusitis, meaning
inflammation of the nose and sinuses; however, for didactic
reasons and for future clinical and research purposes, a differentiation of these entities is preferred. For this purpose, we differentiate between acute rhinosinusitis (ARS), chronic rhinosinusitis (CRS) without polyps and chronic rhinosinusitis with
nasal polyposis (NP), and omit an ill-defined group of hyperplastic chronic rhinosinusitis, which might be included in
CRS, or represent an overlap between CRS and NP.
5-2 Acute rhinosinusitis
The pathophysiology of ARS remains underexplored because
of the difficulty of obtaining mucosal samples during the
course of the disease. Few experimental models have been
dedicated to bacterial infections though experimental models
of viral rhinosinusitis in animals and man exist.(236-238). The common cold is commonly presumed to be implicated in opportunistic bacterial infections due to impairment of mechanical,
humoral and cellular defences and epithelial damage. Usually
two phases of reaction are described: a non-specific phase
where the mucus and its contents (eg: lysozyme, defensin) play
a major role and a second including the immune response and
inflammatory reaction. Common cold symptoms are usually
short- lived with a peak of severity at 48 hours; the course of
bacterial infection appears longer. Some previous studies have
confirmed preferential association and cooperation between
virus and bacteria eg, Influenzae A virus and streptococcal
infection, HRV-14 and S.pneumoniae (239). The mechanism of
this superinfection may be in relation to viral replication which
increases bacterial adhesion. However rhinovirus, the most frequent cause of the common cold is not associated with major
epithelial destruction nor immunosuppression. An initial
mechanism involving release of IL-6 and IL-8 and overexpression of ICAM may be relevant.
5-2-1 Histopathology: inflammatory cells and mediators
From single case reports or a single study including 10 patients
with complications, neutrophils are mainly found in the
mucosa and the sinus fluid (240). Epithelial cells are the first barrier in contact with virus or bacteria. These release and express
several mediators and receptors to initiate different viral elimination mechanisms Recently evidence of biofilms has been
suggested in experimentally-induced bacterial (pseudomonas)
sinusitis in rabbits (241).
5-2-1-1 Epithelial cells
No specific studies are available concerning the role of epithelial cells in ARS. In cases of experimental induced viral rhinosinusitis, epithelial damage is observed. In vitro release of Il-6
after rhinovirus innoculation has been found (242). Epithelial
cells in contact with human rhinovirus express intracellular
adhesion molecule 1 (ICAM-1) which belongs to the
immunoglobulin supergene family. Membranous (m-ICAM)
and circulating (s-ICAM) forms are detected during common
colds and expressed in vitro by epithelial cells (243).
5-2-1-2 Granulocytes
Neutrophils are responsible for proteolytic degradation due to
the action of protease (244). In vitro leucocytes produce lactic
acid during S. pneumoniae induced rhinosinusitis (245) .
Neutrophils are a likely source of IL-8 and TNF- (246).
5-2-1-3 T lymphocytes
These are stimulated during ARS by pro-inflammatory
cytokines such as IL-1, IL-6 and TNF- (247).
Experimentally, antigen stimulated TH2 seems active in the
augmented response to bacterial with S. pneumoniae in allergic mice (236).
5-2-1-4 Cytokines
Mucosal tissue sampled from the maxillary sinus in ARS
(n=10), demonstrated significantly elevated IL-8 concentrations compared to 7 controls (240). IL-8 belongs to the CXCchemokine group and is a potent neutrophil chemotactic protein, which is constantly synthesized in the nasal mucosa (247).
Similar results, though not reaching significance, were
obtained for IL-1 and IL-6, whereas other cytokines such as
GM-CSF, IL-5 and IL-4 were not upregulated. Another study
confirm that some specific cytokines were more implicated in
ARS (IL-12, IL-4, IL-10, IL-13) (248). Recently, IL-8, TNF-alpha
and total protein content were increased in nasal lavage from
subjects with ARS compared to controls and allergic rhinitis
subjects (246). The cytokine pattern found in ARS resembles
that in lavage from naturally acquired viral rhinitis (249).
20
Supplement 20
5-2-1-5 Adhesion molecules

Human rhinoviruses use intercellular adhesion molecule-1
(ICAM-1) as their cellular receptor (250). Expression of cell adhesion molecules are induced by pro-inflammatory cytokines (251).
5-2-1-6 Neuromediators
The role of the nervous system in ARS is not documented but
probably needs further investigation (252). Human axon responses are considered as an immediate protective mucosal defense
mechanism but no specific investigation has been performed
during ARS (253).
5-3 Chronic rhinosinusitis without nasal polyps
5-3-1 Histopathology and inflammatory cells
In the sinus fluid of patients with chronic rhinosinusitis undergoing surgery, the inflammatory cells are predominantly neutrophils, as observed in ARS, but a small number of eosinophils,
mast cells and basophils may also be found (254, 255). The mucosal
lining in chronic rhinosinusitis is characterized by basement
membrane thickening, goblet cell hyperplasia, subepithelial
oedema, and mononuclear cell infiltration. In a recent study
evaluating the percentage of eosinophils (out of 1000 inflammatory cells counted per vision field), 31 patients with untreated
chronic rhinosinusitis without nasal polyps all had less than 10%
eosinophils (overall mean 2%), whereas in 123 untreated nasal
polyp specimen, 108 samples showed more than 10%
eosinophils (overall mean 50%) (256). These observations suggest
that tissue eosinophilia is not a hallmark of chronic rhinosinusitis without polyp formation, and that there are major differences
in the pathophysiology of these sinus diseases.
5-3-1-1 Lymphocytes
T cells, in particular CD4+ T helper cells, participate in the
CRS pathophysiology by being predominant at the initiation
and regulation of inflammation. (257). Epithelial cells from CRS
express functional B7 co-stimulatory molecules (B7-H1, B7H2, B7-H3, and B7-DC) and may contribute in the regulation
of lymphocytic activity at mucosal surfaces (258).
5-3-1-2 Eosinophils
Tissue eosinophilia in CRS has been widely reported as a marker
of inflammation (259), and also shows some relationship to severity
(260)
and prognosis (261). CRS is also accompanied by 3-nitrotyrosine
formation, largely restricted to the eosinophils (262) while Br-Tyr, a
molecular footprint predominantly formed by eosinophil peroxidase-catalyzed tissue damage, may serve as an objective index of
sinus disease activity when compared to healthy mucosa (263).
However, biopsies from paediatric CRS patients show less
eosinophilic inflammation, basement membrane thickening, and
mucous gland hyperplasia than in adults, see section 9 (264).
The association between eosinophil inflammation and the
presence of fungi in CRS has recently been a matter of considerable interest and investigation (148, 149). Eosinophil infiltration
on mucus cytology is correlated with the clinical diagnosis, the
presence of fungal elements on cytology, and serum IgE (265).
No significant correlations between the fungal culture, middle
meatal eosinophilia and clinical parameters of CRS were found
(266)
. In addition, a chronic eosinophilic inflammatory response
to Aspergillus fumigatus is also evoked in a murine model of
CRS, mimicking the human eosinophilic disease (267).
CRS has lower levels of eosinophilic markers [eosinophils,
eotaxin, and eosinophil cationic protein (ECP)] compared with
nasal polyps (268, 269), while round cell infiltration, eosinophils and
plasma cells also differ in CRS and nasal polyp patients (270). All
Table 5-1. Inflammatory cells and mediators in acute rhinosinusitis

author/year
tissue/patients
cells
mediators
technique
conclusions
Rudack 1998 (240)
sinus mucosa acute

RS surgical cases
virus-induced ARS
reovirus
no
IL-8, IL-1, IL-6, IL-5
ELISA
increase IL-8, IL-1, IL-6 during ARS
B cells
T cells
no
histology
IL-6, IL-8,ICAM-1
ELISA
B and Tcells interactions are still

present after D14 and D21 confirming
delayed immune response
HRV promotes internalisation of
S. aureus due to the action of
cytokines and ICAM-1
interference of TH2 cells with immun
response in experimental ARS
Ramadan 2002 (237)
Passariello 2002
(239)
Yu 2004 (236)
Riechelmann 2005 (248)

Perloff 2005 (241)
Khoury 2006 (238)
cell culture epithelial

pneumocyst
mice: S.Pneumoniaeinduced ARS and
allergic sensitsation
nasal secretion
human ARS
maxillary mucosa
rabbits
sinusonasal mucosa
mice S.pneumoniae
mice
eosinophils,
polymorphonuclear cells
infection with
pseudomonas
T lymphocyte
eosinophil
histology
IL-12, IL-4, IL-I0,

IL-13
IHC
differential profile between ARS and

CRS : IL-12, IL-4, IL-10, IL-13
no
electronic
microscopy
nasal lavage
presence of biofilm on mucosa of

maxillary sinus
increase bacterial count when
sensitisation present
bacterials counts
21
these findings suggest that CRS without and with nasal polyps
might be two different disease entities, although they may also
be interpreted as different degrees of inflammation.
5-3-1-5 Neutrophils
In one study, tissue infiltration in CRS was dominated by lymphocytes and neutrophils (274). In another study, eosinophils
dominated in the middle meatal lavages of asthma patients
while neutrophils dominate in the nasal cytology of patients
with small airway disease. Their correlation with lung function
suggests an involvement of the lower airways in CRS (266).
5-3-1-3 Macrophages (CD68+ cells)

There is an increase in the number of macrophages in CRS
and nasal polyps (269) with different phenotypes of macrophages
present in the diseases. The macrophage mannose receptor
(MMR), capable of phagocytosis of invaders and signal transduction for pro-inflammatory mechanisms, might be of importance in CRS immune interactions since MMR shows a higher
expression in CRS than in nasal polyps and controls (271).
5-3-1-4 Mast Cells
Both mast cells (tryptase) and eosinophils (ECP) are involved
in non-allergic and allergic forms of chronic nasal inflammation including CRS (272). Mast cell, eosinophil, and IgE+ cell
numbers are raised in patients with CRS when compared with
controls (273).
5-3-2 Pathomechanisms and inflammatory mediators

A range of mediators and cytokines, namely IL-1, IL-6, IL-8,
TNF-, IL-3, GM-CSF, ICAM-1, MPO and ECP, have been
described as increased in CRS versus control tissue, mostly
from inferior turbinates (278-281). Interestingly, VCAM-1, an adhesion molecule involved in selective eosinophil recruitment,
and IL-5, a key cytokine for eosinophil survival and activity,
were not increased (278, 280). This cytokine and mediator profile
resembles the profile found in viral rhinitis or ARS, with the
exception of a small though significant increase of ECP. This
profile is different from the pattern in nasal polyposis.
Table 5-2. Inflammatory cells in chronic rhinosinusitis without nasal polyps

author/year
Bernardes 2004 (262)
Kramer, 2004 (272)

Muluk, 2004 (257)
tissue/patients
sinonasal mucosa (CRS)
healthy nasal mucosa
sinonasal mucosa (CRS
without NP and wNP)
sinonasal mucosa
(CRS children & adults)
nasal secretions (CRS patients)
Rudack 2004 (276)

Kim, 2005 (258)
sinunasal mucosa (CRS)

sinonasal mucosa
Polzehl, 2005 (270)

without NP and wNP)
Ragab, 2005 (266)
nasal middle meatal lavage

(CRS)
without NP and wNP)
infundibular nasosinusal
mucosa (CRS)
normal ethmoid mucosa
nasal mucosa (CRS
patients & healthy subjects)
mice sensitised to Aspergillus
fumigatus
nasal lavages (CRS patients)
during FESS
without NP and wNP)
Claeys, 2004 (275)

Chan, 2004 (264)
Seiberling, 2005 (277)

Carney, 2006 (273)
Citardi, 2006 (263)
Hafidh, 2006 (265)
Lindsay, 2006 (267)
Ragab, 2006 (153)
Van Zele, 2006 (269)
cell type
eosinophils
technique
IHC
conclusions
CRS: increase of eosinophil activation
macrophages
RT-PCR
eosinophils
lymphocytes
mast cells
healthy turbinate
histology
CRS without NP: MMR mRNA expression

is higher than in NP and controls
CRS in children: eosinophilc inflammation
lower than in adult CRS
mast cells are involved in CRS inflammation
IHC CRS: increase in T lymphocytes
numbers
neutrophils dominate in CRS inflammation
expression of functional B7 costimulatory
molecules
differencial infiltration of inflammatory
cells in both patients groups
neutrophils
nasalepithelial
primary cells
eosinophils, mast cells,
macrophages, B cells,
T cells
neutrophils
uniCAP system
T lymphocytes
IHC
IHC
IHC
nasal cytology
neutrophils dominate in nasal mucosa of

patients with small airway disease
eosinophils
histology, ELISA CRS without NP: lower eosinophilc
inflammation than CRS with NP
mast cells
IHC
CRS: increase of mast cell numbers
compared to controls
eosinophils
mass
CRS: increase of eosinophil activation
spectrometry
fungal spores (mucus) histology
CRS: correlation between nasal
eosinophils (cytology)
eosinophilia and fungal presence
eosinophils
histology
murine CRS model: eosinophil
inflammation mimicks human CRS
eosinophils
histology
CRS: No correlation of fungal culture with
(H&E, GMS)
eosinophilia, and clinical parameters
eosinophils, T cells
IHC
CRS without NP: increased T cells and
decreased eosinophils, compared to NP
IHC:immunohistochemistry; RT-PCR: reverse-transcriptase protein chain reaction; ELISA: enzyme-linked immunosorbent assay; CRS without NP:
chronic rhinosinusitis without nasal polyps; CRS with NP: chronic rhinosinusitis with nasal polyps; H&E: hematoxilin & eosin; GMS: Giemsa)
22
5-3-2-1 Cytokines
IL-8, a highly potent chemoattractant for neutrophils, has been
demonstrated in chronic rhinosinusitis tissue (282) and IL-8 protein concentrations in nasal discharge from chronic rhinosinusitis patients were significantly higher than in allergic rhinitis
patients in a study also involving immunohistochemistry and in
situ hybridization (283). In a study measuring cytokine protein
concentrations including IL-3, IL-4, IL-5, IL-8 and GM-CSF in
tissue homogenates, IL-8 was found to be significantly increased
in ARS, and IL-3 in chronic rhinosinusitis mucosa compared to
inferior turbinate samples (278). IL-3 might be involved in the
local defense and repair of chronically inflamed sinus mucosa by
supporting various cell populations and indirectly contributing
to fibrosis and thickening of the mucosa (284).
In patients with CRS, IL-5, IL-6, and IL-8, and expression in
nasal mucosa is elevated in comparison with healthy
subjects(285). Reports of different types and quantities of inflammatory mediators also support the hypothesis that CRS and
nasal polyps may constitute two different disease entities.
Albumin and IL-5 levels, but not IL-8, are lower in patient with
CRS without than with nasal polyps (286). CRS without nasal
polyps is characterized by a Th1 polarization with high levels of
IFN- and TGF-, while CRS with nasal polyps shows a Th2
polarization with increased IL-5 and IgE concentrations (269).
By assessing biomarker profiles of disease, lower levels of IgE
and IL-5 were found in CRS than in nasal polyps (248). While no
differences were found in IL-6, IL-8, and IL-11, TGF- was
found to be 3 times greater in patients with nasal polyps, as
well as responding more to IL-4, than in patients with CRS
alone (287). Levels of IL-5 and ECP were lower in CRS than in
nasal polyps, and correlated directly with peptide-LTs and
inversely with PGE2 (288).
Patients with CRS show exaggerated humoral and cellular
responses, both of Th1 and Th2 (IL-5, IL-13) types, to common
airborne fungi, particularly Alternaria (152). Using the YAMIK
sinus catheter, both saline or betamethasone decreased IL-1
and IL-8 levels after the 2nd and 3rd weeks of therapy in CRS
patients while TNF- level decreased only in patients treated
with betamethasone (289). Besides the improvement of CRS
symptoms and amelioration of asthma, elevated serum Th2
cytokines (IL-4 and IL-5) were normalized after sinus surgery
(290)
. Staphylococcus aureus exotoxin B increased IL-6 levels in
nasal epithelial cell from patients with CRS (291).
Toll-like receptors (TLR) and the alternate pathway of complement are important components of innate immunity that are
expressed in human sinonasal epithelium. Detectable levels of
TLR mRNA were found in human sinonasal tissue from CRS
patients (292).
An increased expression of TLR2 and proinflammatory
cytokines (RANTES and GM-CSF) was also found in CRS
patients compared with controls (293).
5-3-2-2 Chemokines
In patients with CRS, chemokines have a different expression
Supplement 20
in atopic (increased CCR4+ and EG2+ cells) and non-atopic

(decreased CCR5+ cells), suggesting a potential association of
eosinophil and Th2 cell infiltration in atopic rhinosinusitis (294).
Other chemokines such as growth-related oncogene-alpha
(GRO-alpha) and granulocyte chemotactic protein-2 (GCP-2),
mainly produced by gland and epithelial cells, contribute to
neutrophil chemotaxis in CRS, whereas IL-8 and ENA-78
appear to be of secondary importance (286).
In addition, CCL-20 expression was localized to the epithelial
and submucosal glandular and increased in CRS patients (295).
In patients with maxillary CRS, eosinophilia and vessels
expressing endothelial L-selectin ligands increased during
chronic rhinosinusitis compared with uninflamed control tissue, correlating with the severity of the inflammation (296).
5-3-2-4 Eicosanoids
In CRS patients without NP, COX-2 mRNA and PGE2 were
found to be higher than CRS with nasal polyps while 15Lipoxygenase and lipoxin A4 were increased in all CRS groups
compared with healthy mucosa. LTC4 synthase, 5-lipoxygenase mRNA, and peptide-LT levels were increased in proportion to disease severity (288). CysLT1 receptor expression is
decreased in CRS compared to nasal polyps whereas CysLT2 is
enhanced in both groups compared to healthy controls. Both
receptor levels were correlated to eosinophil numbers, sol-IL5R, ECP, and peptide-LTs. PGE2 protein concentrations and
prostanoid receptors (EP1 and EP3) are up-regulated in CRS
compared to nasal polyps, whereas EP2 and EP4 expression is
enhanced in both diseased groups compared to controls (297).
5-3-2-5 Metalloproteinases and TGF-
The expression of transforming growth factor beta 1 (TGF-1)
at protein and RNA level is significantly higher in CRS without
NP versus CRS with NP and linked to a fibrotic cross anatomy
(298)
. In CRS, MMP-9 and TIMP-1, a natural antagonist, but not
MMP-7 are increased (299), probably resulting in a low MMP-9
activity.
In patients with CRS, MMP-9 concentrations in nasal fluid are
paralleled by MMP-9 in extracellular matrix (ECM) and independently predicted by the number of neutrophils and
macrophages in the tissue, but not related to fibrosis, number
of myofibroblasts, or TGF-1 expression (300).
Several findings also suggest different histopathological characters between CRS and nasal polyps. CRS is histologically characterized by fibrosis and reflected by an increased expression of
TGF-1 compared with nasal polyps, suggesting a potential differentiation between these two entities (301). In CRS and nasal
polyp tissues, the expression of TGF-1, MMP-7, MMP-9, and
TIMP-1 was increased compared with controls while TGF-1
and TIMP-1 were higher in CRS and MMP-7 in nasal polyps (302).
After sinus surgery, MMP-9 and TGF-1 were initially
increased and healing quality correlated to preoperative MMP-
23
9 levels in nasal secretions. MMP-9 was also lower in patients

with good healing compared to those with poor healing, suggesting MMP-9 as a potential factor to predict and monitor
healing quality after sinus surgery (303). Clarithromycin therapy
also reduces cellular expression of TGF- and NFB in biopsies from CRS patients (304).
5-3-2-6 Immunoglobulin
IgE+ cell numbers are raised in patients with allergic, fungal,
and eosinophilic CRS when compared with controls (273). In a
clinical trial, preoperative total IgE levels showed a significant
correlation with the extent of disease on sinus CT, without any
change one year after sinus surgery (308). IgG antibodies to
Table 5-3. Inflammatory mediatos (cytokines, chemokines, toll-like receptors, adhesion molecules, eicosanoids, and matrix metalloproteinases) in
chronic rhinosinusitis without nasal polyps
author, year
Ruback, 2004 (276)
tissue, patient
sinonasal mucosa (biopsies)
marker
IL-5, IL-8
technique
ELISA
conclusion
CRS without NP: lower levels of IL-5 but
not IL-8 than in NP
Shin 2004 (152)
PBMC from CRS (in vitro)
IFN-, IL-5, IL-13
ELISA
Van der Meer, 2004 (292)
sinonasal mucosa
toll-like receptors
(TLR)
RT-PCR
exposure to Alternaria increase cytokine

levels
TLR are expressed in CRS
Wallwork, 2004 (304)
CRS nasal mucosa

(in vivo & in vitro)
TGF-1, NFkB
IHC
clarythromycin inhibites TGF-1 and

NFkB only in vitro
Watelet, 2004 (301)
sinonasal mucosa (FESS)
TGF-1
IHC
CRS without NP: increased expression of
Watelet, 2004 (303)
MMP-9, TGF-1
IHC
correlation with the tissue healing quality
Bradley, 2005 (287)
sinunasal mucosa (FESS)
TGF-
RT-PCR
CRS without NP: lower expression of
Elhini,2005 (294)
ethmoidal sinus mucosa
CCR4+, CCR5+
IHC
Real Time PCR
TGF- than in NP
CRS patients: increase of CCR4+ in atopics
and decrease of CCR5+ in non-atopics
Furukido, 2005 (289)
IL-1, IL-8, TNF-
ELISA
Prez-Novo, 2005 (288)
sinus lavage (with YAMIK

catheter)
sinonasal mucosa
IL-5
ELISA
Riechelmann, 2005 (248)
nasal secretions
15 cytokines (IL-5)
ELISA
Toppila-Salmi, 2005 (296)
L-selectin ligands
IHC
IL-6
ELISA
SA enterotoxin B increases IL-6 in CRS
Lane, 2006 (293)
maxillary sinus mucosa

(surgery)
CRS primary epithelial cells
(cultures)
ethmoidal mucosa (surgery)
betamethasone and Saline decrease

cytokine levels
CRS without NP: lower levels of IL-5 and
ECP than in NP
CRS without NP: lower levels of IL-5 than
in NP
increased expression in CRS endothelial cells
real time PCR
increase in CRS compared to healthy controls
Lee, 2006 (295)
sinonasal mucosa
TLR2, RANTES,
GM-CSF
CCL 20
Lin, 2006 (305)
sinunasal mucosa (FESS)
IL-4, IL-5
IHC
Real Time PCR
ELISA
increased expression of CCL-20 in CRS

without NP
sinus surgery increases cytokine levels
Rudack, 2006 (286)
sinonasal mucosa
sinonasal mucosa
Prez-Novo, 2006 (297)
nasal mucosa
Watelet, 2006 (306)
CysLT receptors
EP Receptors
MMP-9
HPLC +
bioassay
real time PCR
ELISA
real time PCR
expression of GRO- and GCP-2 in CRS
Prez-Novo, 2005 (288)
GRO-, GCP-2, IL-8,

ENA-78
COX-2 PGE2
Lu, 2005 (302)
sinonasal mucosa (surgery)
MMP-7, MMP-9,
TGF-1 compared to NP
Damm, 2006 (291)
TIMP-1, TGF-1
Van Zele, 2006 (307)
sinonasal mucosa
Xu, 2006 (285)
sinonasal mucosa
INF-, TGF-
IHC
ELISA
ELISA
UniCAP system
IL-5, IL-6, IL-8, NFkB ELISA
RT-PCR
CRS without NP: COX-2 and PGE2 are

more expressed than in NP
CRS without NP: CysLT and EP receptors
are more expressed than in NP
there exists a correlation between MMP-9
expression and tissue healing quality
there exists a diffeernt profile expression in
CRSwo NP, nasal polyps, and healthy
mucosa
There is a TH1 polarization in CRS
without NP
cytokines are increased in CRS compared
to healthy controls
FESS: functional endoscopic sinus surgery; Immunohistochemistry: CRS without NP: chronic rhinosinusitis without nasal polyps, CRS with
NP:chronic rhinosinusitis with nasal polyps; RT-PCR: reverse-transcriptase protein chain reaction; ELISA: enzymo-linked immunosorbent assay
24
Supplement 20
Alternaria and Cladosporium are clearly increased in patients

with CRS compared with normal individuals while less than
30% of CRS patients have specific IgE antibodies to Alternaria
or Cladosporium (152). Fungal-specific IgG (IgG3) and IgA levels
(to Alternaria alternata and Aspergillus fumigatus), but not
IgE, are higher in CRS with eosinophilic mucus compared with
healthy volunteers, challenging the presumption of a unique
pathogenic role of fungal allergy in allergic fungal sinusitis
(150)
.
5-3-2-7 Nitric Oxide (NO)
CRS epthelial cells show a stronger expression of TLR-4 and
iNOS than controls, iNOS being upregulated in nasal epithelium and correlated with TLR-4 (309). In a prospective randomized
trial in patients with CRS who had failed initial medical therapy with nasal corticosteroids, the rise in nNO seen on both
medical and surgical treatments correlated with symptom
score, saccharin clearance time, endoscopic changes, and polyp
size, suggesting that nNO provides a non-invasive objective

measure of the response of CRS to therapy on an individual
basis (310). However, some contradictory results on the role of
nNO on nasal inflammation have been recently assessed (311).
5-3-2-8 Neuropeptides
Neurogenic inflammation may play a potential role on the
manifestation of chronic rhinosinusitis (312). In addition, CGRP
(trigeminal sensory) and VIP (parasympathetic) levels in saliva
were significantly elevated between attacks in patients with the
diagnosis of allergic CRS and migraine compared to controls ,
returning to baseline after pseudoephedrine therapy but only
in CRS patients (313).
5-3-2-9 Mucins
Airway mucus is overproduced in CRS. Mucins are the major
components of mucus and the macromolecules that impart rheologic properties to airway mucus. MUC5AC and MUC5B are
Table 5-4. Inflammatory mediators (immunoglubulins, nitric oxide, neuropeptides, mucins, and others) in Chronic Rhinosinusitis without nasal polyps
author, year
Kim, 2004 (314)
tissue, patient
maxillary sinonasal mucosa
Lee, 2004 (317)
maxillary sinonasal mucosa
Maniscalco, 2004 (324)
allergic rhinitis patients
Shin, 2004 (152)
PBMC from CRS (in vitro)
Wang, 2004 (309)
sinonasal mucosa
Ali, 2005 (316)
CRS patients (sinusal mucus)
Pant, 2005 (150)

Sun, 2005 (321)
Bellamy, 2006 (313)
CRS patients (serum)

CRS patients (sinus effusions,
nasal secretions, serum)
allergic CRS (saliva)
Carney, 2006 (273)
infundibular sinonasal mucosa
Lal, 2006 (308)

Martnez, 2006 (319)
CRS patients (serum)

Pena, 2006 (320)

Ragab SM, 2006 (310)
children with CRS

(sinonasal mucosa)
CRS patients
Viswanathan, 2006 (315)
CRS patients (nasal mucus)
Hu, 2007 (322)
children with CRS

(sinonasal mucosa)
Lee, 2006 (323)
marker
MUC5AC, MUC5B
technique
RT-PCR
conclusion
increased in CRS compared to healthy
controls
MUC8
RT-PCR
MUC8 is upregulated in CRS compared to
controls
nasal NO
chemi-luminenNO during humming is a reliable marker
scence
of sinus patency
fungal IgG
UniCAP system IgG is increased in CRS compared to
healthy controls
TLR4, iNOS
in-situ
TLR4 and iNOS are increased in CRS
hybridization
compared to healthy controls
MUC5AC, MUC2
ELISA
increase of MUC5AC and decrease of
MUC2 in CRS
fungal IgG, IgA
ELISA
IgG3 and IgA are increased in CRS
VEGF
ELISA
VEGF expression is higher in the sinus
mucosa than in nasal mucosa and serum
VIP, CGRP
radioimmunoneuropetides are increased in acute attacks
assay
IgE+ cells
immunoIgE+ cells are increased in CRS compared
histochemistry
to healthy controls
total IgE
ELISA
correlation of IgE levels with the CRS extent
MUC1, MUC2, MUC4 IHC
MUC5AC, MUC5B
In situ
there exist different MUC expression
hybridization
patterns depending on the sinonasal disease
MUC5AC
IHC
MUC5AC is expressed in the epithelium
but not in submucosal glands
nasal NO
chemimedial and surgical treatments increase
luminescence
nNO, with correlation with nasal symptoms
MUC5AC, MUC5B
ELISA
increased in CRS compared to healthy
controls
VEGF
IHC
CRS without NP: lower expression of
VGEF compared to NP
surfactant protein-A
RT-PCR
increased expression of SP-A in CRS
compared to healthy controls
FESS: functional endoscopc sinus surgery; IHC:immunohistochemistry; CRS without NP:chronic rhinosinusitis without nasal polyps; CRS with
NP:chronic rhinosinusitis with nasal polyps; RT-PCR: reverse-transcriptase protein chain reaction; ELISA: enzymo-linked immunosorbent assay
25
Table 5-5. Biofilms in chronic rhinosinusitis

author, year
Cryer, 2004 (329)
population
Adults with CRS (n=16) Biopsies of mucosa
Perloff, 2004 (330)
Frontal recess stents from post FESS adults (n=6)
Ferguson, 2005 (331, 467)
Adults with CRS (n=4)

TEM of Biospies of mucosa
Rabbit model of P.aeruginosa (type IV pili
mutants) maxillary sinusitis (n=4) SEM of mucosa
Rabbit model of P.aeruginosa maxillary sinusitis
(n=22)
Palmer, 2005 (332)

Perloff,
(241)
Ramadan, (333)
Sanclement, (334)
Bendouah, 2006 (335)
Bendouah, 2006 (336)
Sanderson, (337)
Zuliani, (338)
evidence for biofilms in CRS

Morphological evidence of EPS seen on four of the specimens and
of bacteria in one on SEM
All six had biofilm morphology on SEM and five had cultures with
S.aureus
Morphologic evidence of biofilm in two of the samples on TEM
Biofilm not seen in sinusitis model with bacteria defective with type
IV pili (impaired attachement). Increased CBF seen in response.
All clinically had sinusitis. 21 cultured P.aeruginosa. Morphological
evidence of biofilm seen in all on SEM No biofilm seen in the 22
contraleteral controls
Adults with CRS (n=5) SEM of Mucosal biopsies All 5 had morphological evidence of biofilms based on SEM
Adults with CRS (n=30) controls (n=4)
Morphological evidence of biofilms seen in 24 patients. No controls
SEM/TEM of mucosal biopsies
positive.
Adults with CRS (n=19)
22 of 31 isolates of S. Aureus, Coagulase negative Staphylococcal
Semi quantitative in vitro culture assessment
Species, P. aeruginosa demonstrated biofilm forming capacity in vitro
Adults with CRS (n=19) Semi quantitative in vitro Correlates above data with a dichotomous outcome of poor or
culture assessment
favourable based on symptoms and endoscopic signs.
Poor outcome overrepresented in patients with biofilm forming
isolates
Adults with CRS (n=18) controls (n=5)
FISH for S. pneumoniae, S. aureus, H. influenza and P. aeruginosa
FISH visualised with confocal microscopy of
and standard cultures
mucosal biopsies
14 of 18 had evidence of biofilm and 2 of 5 controls.
Cultures did not correlate.
Children with CRS and OSA (n=16 )
All 8 CRS patients had biofilms in the adenoids. No control
Adenoid samples
demonstrated significant biofilm coverage.
FESS: functional endoscopic sinus surgery; SEM:scanning electron microscopy; TEM:transmission electron microscopy; OSA:obstructibe sleep
apnoea FISH:fluorescent in situ hybridisation
increased in CRS compared with healthy sinus mucosa (314, 315).

MUC5AC and MUC5B represent the major mucin component
in sinus while MUC5B and MUC2 predominated in healthy
mucosa. In CRS, upregulation of MUC5AC was associated
with downregulation of MUC2 and vice versa (316). MUC8
expression is also increased in CRS compared with healthy
maxillary sinus mucosa (317). In a comparative study between
different upper airways pathologies CRS with nasal polyps had
a different pattern of mucin expression (increased MUC1 and
MUC4, and decreased MUC5AC) compared to healthy
mucosa while cystic fibrosis CRS (increased MUC5B) and
antrochoanal polyps (decreased MUC2) also expressed a different pattern from CRS with nasal polyps (318, 319). Moreover, the
number of goblet cells expressing MUC5AC mucin does not
differ in children with and without CRS (320).
5-3-2-10 Other mediators
Vascular endothelial-cell growth factor (VEGF) is produced in
paranasal sinuses and nasal mucosa and it has been found to
be increased in patients with CRS. Hypoxia is associated with
VEGF production by nasal fibroblasts and TNF- ?and endotoxin may synergistically enhance VEGF production in
paranasal sinuses under hypoxic conditions (321). In children,
VEGF expression was shown to be lower within CRS mucosa

than in nasal polyps (322). Surfactant protein A (SP-A), a protein
that appears to play an important role in mammalian first-line
host defense, was found to be increased in sinus mucosa of
CRS patients compared with healthy sinus mucosa (323).
5-3-2-11 Biofilms
The conversion of free-floating planktonic bacterial forms into
complex sessile communities has been extensively investigated. Biofilms are structured, specialised communities of adherent micro-organisms encased in a complex extra-cellular polymeric substance (EPS) (325).There is no one common biofilm
structure with bacteria responding to environment and intrinsic genetic programming. These influences and cell-cell signalling that exists between bacteria in close proximity (quorum
sensing) facilitates the development of the biofilm phenotype
(326)
. Although the bacteria per se may be susceptible to antibiotics, the adoption of a biofilm strategy is protective resulting
in chronic and recalcitrant infectious processes. Biofilms have
been found in otitis media, cholesteatoma and tonsillitis (327).
There are presently 11 papers in the literature showing evidence for biofilm formation in CRS (328).
26
5-4 Chronic rhinosinusitis with nasal polyps

5-4-1 Histopathology and inflammatory cells
Histomorphological characterisation of polyp tissue reveals frequent epithelial damage, a thickened basement membrane,
and oedematous to sometimes fibrotic stromal tissue, with a
reduced number of vessels and glands, but virtually no neural
structure (339-341). The stroma of mature polyps is mainly characterised by its oedematous nature and consists of supporting
fibroblasts and infiltrating inflammatory cells, localized around
empty pseudocyst formations. Among the inflammatory
cells, EG2 (activated) eosinophils are a prominent and characteristic feature in about 80% of European polyps (342), whereas
lymphocytes and neutrophils are the predominant cells in cystic fibrosis and in CRS without NP. Eosinophils are localised
around the vessels, glands, and directly beneath the mucosal
epithelium (340). However, neutrophils are also a constant finding in nasal polyps, and their number is increased compared to
controls (269). Furthermore, increased numbers of activated Tcells and plasma cells characterize the typical cell composition.
In small polyps, not larger than 5 mm, growing on normal
looking mucosa of the middle turbinate in patients with bilateral polyposis, the early processes of polyp growth have been
studied (343). Numerous subepithelial EG2+ eosinophils were
present in the luminal compartment of the early stage polyp,
forming a cap over the central pseudocyst area. In contrast,
mast cells were scarce in the polyp tissue, but were normally
distributed in the pedicle and the adjacent mucosa, which had
a normal appearance. This contrasts to mature polyps, where
degranulated mast cells and eosinophils are often diffusely distributed in the polyp tissue. Fibronectin deposition was
noticed around the eosinophils in the luminal compartment of
the early stage polyp, was accumulated subepithelially, and
formed a network-like structure in the polyp centre and within
the pseudocysts. The presence of myofibroblasts was limited to
the central pseudocyst area. Interestingly, albumin and probably other plasma proteins were deposited within the pseudocysts, adjacent to the eosinophil infiltration. These observations suggest a central deposition of plasma proteins, regulated
by the subepithelial eosinophilic inflammation, as a pathogenetic principle of polyp formation and growth.
5-4-1-1 Lymphocytes
Nasal polyps show a significantly increased number of T-lymphocytes (CD3) and activated T-lymphocytes (CD25) compared to control patients (269). In non-allergic CRS with nasal
polyps a tendency to fewer CD4+ cells in the epithelium and
more CD8+ cells in the lamina propria was found (344). An
inverse median ratio of CD4+/CD8+ T cells as compared to
the middle turbinate of control subjects was found in one
recent study (345). Functional studies on T-cells, especially T regulatory cells, are lacking so far. Interestingly, there were almost
no nave B-lymphocytes (CD20) present in the tissue, although
Supplement 20
a significantly higher number of plasma cells (CD138) was present in NP versus controls and CRS without polyps (269, 346). This
fact is reflected by a significant increase in immunoglobulin A,
G and E synthesis (van Zele, unpublished).
S. aureus superantigens (SAgs) bind the V beta-region of the
T-cell receptor (TCR) outside the peptide-binding site.
Approximately 50 distinct V beta-domains exist in the human
repertoire, and distinct SAgs will bind only particular domains,
generating a pattern of V beta-enrichment in lymphocytes
dependent on the binding characteristics of a given toxin. Flow
cytometry was used to analyze the V beta-repertoire of polypderived CD4+ and CD8+ lymphocytes in the light of the
known skewing associated with SAg exposure. Seven of 20
subjects exhibited skewing in V beta-domains with strong associations to S. aureus SAgs. This study establishes evidence of
S. aureus SAg-T-cell interactions in polyp lymphocytes of 35%
of CRS with NP patients (347).
5-4-1-2 Eosinophils
An increased number of eosinophils, demonstrated by HE staining or EG2 IHC, is a hallmark of Caucasian NPs. Eosinophil
numbers are significantly higher in NP tissue compared to CRS
(348)
and other sinus disease and control mucosa, and are further
increased in patients with co-morbid asthma and/or aspirin sensitivity, but independent from atopy (192, 349). In a study evaluating
the percentage of eosinophils (out of 1000 inflammatory cells
counted per vision field), 31 patients with untreated chronic
sinusitis without nasal polyps all had less than 10% eosinophils
(overall mean 2%), whereas in 123 untreated nasal polyp specimen, 108 samples showed more than 10% eosinophils (overall
mean 50%) (350). Generally, the differences in ECP measurement
between diseases are more pronounced than the cell numbers,
indicating a more intense activation of eosinophils in polyps.
However, the eosinophilic inflammation in nasal polyp tissue
from China, as measured by ECP and cytokine/chemokine levels (IL-5, eotaxin), was not significantly different from control
tissue, and was significantly lower compared to Caucasian
polyps. The semi-quantitative scores for EG2+ eosinophils were
0,45+1.15 for the Chinese polyp patients and 1,95 2,85 for the
Caucasian polyp patients, being significantly different (346).
Furthermore, eosinophil numbers are not different from controls and cystic fibrosis polyps (269).
5-4-1-3 Macrophages and dendritic cells
Macrophage numbers seem to be slightly increased in nasal
polyps, and these cells express increased amounts of
macrophage mannose receptors (MMR), an innate pattern recognizing receptor, capable of phagocytosis of invaders and signal transduction for proinflammatory mechanisms (275). There
also is a higher number of macrophages in patients with CF
than in patients with CRS or in controls (351). Our knowledge on
dendritic cells is very limited; they are present in nasal polyps,
and express the high affinity IgE receptor (344, 352).
Table 5-6. Inflammatory cells in Chronic Rhinosinusitis with nasal polyps (IHC; immunohistochemistry; RT-PCR; reverse-transcriptase protein
chain reaction; ELISA: enzymo-linked immunosorbent assay)
author, year
Fokkens, 1990
cell type
T lymphocytes
B lymphocytes
eosinophils
neutrophils
dendritic cells
Ig+ cells
eosinophils
technique
IHC
conclusion
IHC
mast cells
IHC
nasal polyps
nasal polyps
dendritic cell
IHC
CRS with NP: more than 10% eosinophils

compared to CRS without NP
greater mast cell degranulation in CRS
with NP compared to healthy inferior
turbinate
dendritic cells are present in NP
endothelial cells
flow cytometry
RT-PCR
nasal polyps
nasal polyps
mast cells
fluorescence
microscopy
ELISA
RT-PCR
nasal polyp from cystic

fibrosis (CF)
NP from non-CF
nasal polyps
eosinophils from healthy
volunteers incubated with CRS
with NP polyp epithelial cell
nasal polyps
neutrophils
IHC
endothelial cells
IHC
epithelial cells
ELISA
epithelial cells
IHC
RT-PCR
nasal polyps
nasal polyps
macrophages
real-time
RT-PCR
epithelial cells
IHC
Gosepath, 2005 (363)
nasal polyps
endothelial cells
IHC
Kowalski, 2005 (355)
nasal polyps
Conley, 2006 (365)
nasal polyps
antrochoanal polyp
nasal polyps
nasal polyps
nasal polyps
epithelial cells, stem

cell factor (SCF)
S. aureus superantigens
of the T-cell receptor
T lymphocytes
ELISA
RT-PCR
flow cytometry
epithelial cells
IHC
ELISA
T lymphocytes
plasma cells
eosinophils
neutrophils
IHC
epithelial cells
flow cytometry
RT-PCR
(344)
Jankowski, 1996
(350)
Drake-Lee, 1997 (354)
Haas, 1997 (352)

Jahnsen, 1997 (361)
Loesel, 2001 (353)

Seong, 2002
(359)
Sobol, 2002 (351)
Wittekindt, 2002 (362)

Shin, 2003 (356)
Chen, 2004
(364)
Claeys, 2004
(271)
Watanabe, 2004 (358)
Hao, 2006
(345)
Schaefer, 2006
(357)
Van Zele, 2006 (269)
Ramanathan, 2007 (366)
tissue, patients
nasal polyps
allergic rhinitis nasal mucosa
nasal polyps
nasal polyps
inferior turbinate
nasal polyps
epithelial cells
IHC
endothelial cells express VCAM-1, induced

by IL-4 and IL-13, with a role in eosinophils
and T lymphocyte recruitment
number of mast cells is not different
between controls and CRS with NP
In CRS with NP: inflammatory mediators
may over-express MUC8 mRNA in NP and
downregulate MUC5AC
there is a neutrophil massive activation in
CF-NP compared to non CF-NP
VPF/VEGF expression was higher in NP
than in healthy nasal mucosa
eosinophils in nasal secretions are activated
by GM-CSF, which is produced by nasal
epithelial cells
CRS with NP epithelial cells express
increased amounts of LL-37, an
antimicrobial peptide
CRS with NP: MMR has a higher
expression than in CRS without NP and
controls
clinical efficacy of glucocorticoids on NP
epithelial GM-CSF production, which
prolongs eosinophil survival.
VPF/VEGF are increased in NP compared
to healthy nasal mucosa, suggesting a role
in both the formation of NP and induction
of tissue edema
epithelial cells release stem cell factor (SCF)
S. aureus SAg-T-cell interactions in 35% of
CRS with NP lymphocytes
inverse median ratio of CD4+/CD8+ T
cells as compared to the middle turbinate
NP endothelial and epithelial cells are the
main source of CC chemokine eotaxin-2
CRS with NP: increase in T lymphocytes
numbers and activated T-lymphocytes,
CD4+/CD8+ T cells, and eosinophils than
CRS without NP and controls.
CRS with NP: increased number of
neutrophils and more MPO compared to
healthy controls but not to CRS without NP
TLR9 is down-regulated in NP epithelial
cells and involved in innate immunity
functions
28
5-4-1-4 Mast Cells

The number of mast cells is not different between controls and
nasal polyps, these cells are however more often IgE-positive,
especially in asthmatics, independent of atopy (353). There was
greater mast cell degranulation in the nasal polyp compared to
inferior turbinate (354). The density of mast cells in the epithelial
and stromal layers of nasal polyps correlated with the expression of SCF mRNA and protein in the supernatants of NP
epithelial cells (355).
5-4-1-5 Neutrophils
There is an increased number of neutrophils and higher concentrations of MPO protein in nasal polyps vs. controls, but
not compared to CRS without polyps, and both parameters are
even higher in CF NPs (269, 351) indicating a massive activation in
CF- NPs compared to non-CF-NPs. The role of neutrophils
currently is not understood in NPs.
5-4-1-6 Epithelial cells
Human nasal epithelial cells contain and secrete IL-8, GMCSF, eotaxin, eotaxin-2 and RANTES, and thus may provide
enough growth factors to attract eosinophils (356, 357), with GMCSF being important for the survival of those cells (358).
Epithelial cells also release stem cell factor (SCF), a cytokine
with chemotactic and survival activity for mast cells, with the
expression of SCF mRNA correlating to SCF protein, and with
the density of mast cells in epithelial and stromal layers of
nasal polyps (355).
Inflammatory mediators may lead to over-expression of MUC8
mRNA in nasal polyps and downregulation of MUC5AC
mRNA expression, and influence the composition of mucus in
polyp disease (359). Nasal polyp epithelial cells also express
increased amounts of LL-37, an antimicrobial peptide (360), but
down-regulate the level of TLR9 expression (347), and are thus
directly involved in innate immunity functions.
5-4-1-7 Endothelial cells (See also adhesion molecules)
Endothelial cells express VCAM-1, induced by IL-4 and IL-13,
which plays an important role for the preferential recruitment
of eosinophils and T lymphocytes (361). However, a key phenomenon in nasal polyps is the remarkable oedema, which
awaits explanation. Vascular permeability/vascular endothelial
growth factor (VPF/VEGF) plays an important role in inducing angiogenesis and modulating capillary permeability. In fact,
the expression of VPF/VEGF in specimens of nasal polyps
was significantly stronger than in specimens of healthy nasal
mucosa of controls (362). VPF/VEGF in polypous tissue was
mainly localized in vascular endothelial cells, in basal membranes and perivascular spaces, and in epithelial cells. The
markedly increased expression in nasal polyps as opposed to
healthy nasal mucosa suggests that VPF/VEGF may play a significant role in both the formation of nasal polyps and in the
induction of heavy tissue oedema (363).
Supplement 20
5-4-2 Pathomechanisms and Inflammatory Mediators

5-4-2-1 Cytokines
A large body of studies has focused on eosinophilic mediators
in nasal polyp tissue, and demonstrated that different cell types
generate these mediators. Early studies by Denburg et al (367)
demonstrated that conditioned medium, derived from cultured
nasal polyp epithelial cells, contained potent eosinophil
colony-stimulating activities, as well as an interleukin-3-like
activity. The authors suggested that accumulation of
eosinophils in polyps may partly be a result of differentiation
of progenitor cells stimulated by soluble haemopoietic factors
derived from mucosal cell populations. An increased synthesis
of GM-CSF by epithelial cells, fibroblasts, monocytes, and
eosinophils was suggested later (99, 368-370). According to Hamilos
et al (30), polyp tissue samples from patients with or without
allergy contained different cytokine profiles. Other studies
involving protein measurements in tissue homogenates could
not support these findings (31, 278).
In contrast, IL-5 was found to be significantly increased in
nasal polyps, compared to healthy controls, and the concentration of IL-5 was independent of the atopic status of the patient.
Indeed, the highest concentrations of IL-5 were found in subjects with non-allergic asthma and aspirin sensitivity.
Furthermore, eosinophils were positively stained for IL-5, suggesting a possible autocrine role for this cytokine in the activation of eosinophils, and a strong correlation between concentrations of IL-5 protein and eosinophilic cationic protein (ECP)
was demonstrated later (192). The key role of IL-5 was supported
by the finding that treatment of eosinophil-infiltrated polyp tissue with neutralizing anti-IL-5 monoclonal antibody (mAB),
but not anti-IL-3 or anti-GM-CSF mAbs in vitro, resulted in
eosinophil apoptosis and decreased tissue eosinophilia (371).
Collectively, these studies suggest that increased production of
IL-5 is likely to influence the predominance and activation of
eosinophils in nasal polyps independent of atopy. The lack of
difference in the amounts of cytokines detected in polyps from
allergic or non-allergic patients was meanwhile supported by
several other studies (372, 373). Furthermore, Wagenmann et al (374)
demonstrated that both Th1 and Th2 type cytokines were
upregulated in eosinophilic NP, irrespective of allergen skin
test results.
Recently, the regulation of the IL-5 receptor, which exists in
the soluble and transmembrane isoform, has been investigated
(375)
. Whereas the probably antagonistic soluble isoform is
upregulated, the signal transducing transmembrane isoform is
down-regulated in nasal polyps, especially if associated with
asthma.
5-4-2-2 Chemokines
Recent studies have also shown that nasal polyps also express
high levels of RANTES and eotaxin, the predominant recognised eosinophil chemoattractants. Bartels and colleagues (376)
demonstrated that expression of eotaxin- and RANTES
29
mRNA, but not MCP-3 mRNA, was elevated in non-atopic

and atopic nasal polyps, when compared to normal nasal
mucosa. Similarly, several publications demonstrated an
increased mRNA expression for eotaxin, eotaxin-2, eotaxin-3,
and MCP-4 (357, 377-379). The expression of eotaxin-2, a CCR3-specific chemokine, was found to be the most prominent of the
three chemokines investigated. According to other data (31, 192, 343),
it appears that eotaxin, rather than RANTES, in cooperation
with IL-5, plays a key role in chemo-attraction and activation
of eosinophils in NP tissue. This is in accordance with the findings of a recent extensive study of about 950 non-allergic and
allergic polyp patients, which has also suggested that nasal
polyp eosinophilic infiltration and activation may correlate
mainly with increased eotaxin gene expression, rather than
with RANTES expression (380). The excessive production of
eotaxin in nasal polyps was recently confirmed in comparison
to controls and CRS patients (269).
prostaglandins, in nasal polyps is characterized by a deficit in

the production of PGE2 compared to CysLT levels (297, 393-395).
This phenomenon was also observed in nasal polyp tissue and
peripheral blood from aspirin-intolerant subjects (396), and cyclooxygenase (COX)-2 mRNA expression and NF-kB activity
were markedly lower in nasal polyp tissue from aspirin intolerant subjects compared to tolerant patients (397, 398). However, our
recent data indicate that levels of PGE2 inversely correlate
with the degree of eosinophilic inflammation in nasal tissue
from aspirin intolerant, but also tolerant patients. These findings support previous studies, (395, 399) and suggest that this downregulation may again represent a bystander phenomenon
linked to the severity of the inflammatory process. Of interest,
research on prostanoid E (EP) receptor regulation has recently
been performed, with controversial results. A down-regulation
of EP1 and EP3 and an upregulation of EP2 and EP4 receptors in nasal polyp tissue compared to normal nasal mucosa
was shown (297). It is known that EP2 and EP4 are highly
expressed on eosinophils and a deficiency of PGE2 production
may up-regulate the expression of these receptors. However,
the expression of EP2 and EP4 receptors did not correlate with
eosinophil numbers or eosinophil activation markers, indicating that the regulation of these receptors may involve other
cellular sources. This was recently confirmed by Ying et al.
who showed the expression of EP receptors in a variety of
inflammatory cells in the nasal mucosa (400). These authors
found a down-regulation of the EP2 receptor in aspirin intolerant patients and speculated on the effects on the production of
inflammatory mediators. However, PGD2 may also mediate
eosinophil chemotaxis and activation and the production of
cytokines such as interleukins IL-4, IL-5, and IL-13 by human
Th2 inflammatory cells via different receptors, e.g. via the
CRTH2 receptor (401, 402). The relative contributions of EP and
other PG receptors is far from being unravelled, and so far, little points to a specific change in PG regulation in aspirin-intolerant subjects.
Finally, lipoxins are generally associated with anti-inflammatory effects and have been reported to reduce leukocyte infiltration (403). However, certain di- hydroxyeicosatetraenoic acids
(HETEs), which are precursors of these molecules, may have
also pro-inflammatory effects, specifically neutrophilic and
eosinophilic chemotaxis (404). Nasal polyp tissue has been shown
to have a high capacity to produce LXA4 after incubation with
exogenous LTA4 in the presence of polymorphonuclear granulocytes (405). In addition, severity of asthma has been associated
with increased expression and activation of the 15- LO (lipoxygenase) enzyme, collagen deposition and eosinophil accumulation (406). Interestingly, the capacity to produce lipoxins is
decreased in epithelial cells from patients with aspirin intolerance (407). These results are in line with those showing that
basal levels of this enzyme are increased in nasal polyp tissue
of aspirin-tolerant, but down- regulated in aspirin intolerant
subjects. 15-LO and LXA4 levels were increased in all chronic
sinus disease groups, but significantly down-regulated in

Studies of cell adhesion molecules are relatively few. Early
studies by Symon and colleagues (381) demonstrated that ICAM1, E-selectin and P-selectin were well expressed by nasal polyp
endothelium, whereas VCAM-1 expression was weak or
absent. An elegant study by Jahnsen et al (382), employing threecolour immunofluorescence staining, has however demonstrated that both the number of eosinophils and the proportion of
vessels positive for VCAM-1 were significantly increased in
nasal polyps compared with the turbinate mucosa of the same
patients. Moreover, treatment with topical glucocorticosteroids
decreases the density of eosinophils and the expression of
VCAM-1 in polyps (383). The interaction between VLA-4 on
eosinophils and VCAM-1 on endothelial cells may not only be
of particular importance for transendothelial migration of
eosinophils, but may also modify their activation and effector
functions (384).
5-4-2-4 Eicosanoids
Levels of leukotrienes and their receptors have been shown to
be up-regulated in nasal polyp tissue (385, 386), more pronounced
in patients with intolerance to aspirin (288, 387, 388). A recent study
suggested that high levels of LTC4 synthase are directly linked
to the manifestation of aspirin intolerance (389), and polymorphisms linked to this enzyme have been suggested to cause the
syndrome (390). However, up-regulation of cysteinyl-leucotrienes
(CysLTs) does occur in chronic rhinosinusitis even in the
absence of clinical aspirin sensitivity and appears to be closely
related to the severity of eosinophilic inflammation (IL-5 and
ECP), a hallmark of nasal polyp disease (288). Increased expression of the CysLT1 and CysLT2 receptors have been demonstrated on inflammatory cells in nasal polyp tissue (297, 391, 392), but
also inflammatory cells in nasal lavage from patients with allergic rhinitis (393). Thus, the regulation of CysLTs does not seem
to be a pathognomonic feature of aspirin intolerance.
The regulation of the cyclo-oxygenases and their products, the
30
patients with aspirin intolerance, suggesting a specific regulation in this subgroup (297).
Summarizing, eicosanoid changes in paranasal sinus diseases
are generally characterized by an upregulation of CysLTs,
LXA4 and PGD2 and a downregulation of COX-2 and PGE2.
Eosinophilic markers such as ECP and IL-5 correlate directly
with LTC4/D4/E4 and inversely with PGE2 concentrations,
demonstrating the close relationship to severity of inflammation. In the sinus mucosa of aspirin intolerant subjects, these
changes might be extreme, as the degree of inflammation is
maximal, and the clinically apparent aspirin intolerance triad
may be dependent on severe inflammation in the airways. In
contrast, specific changes such as a relative down-regulation of
lipoxin LXA4 in those patients is less obvious, as they possibly
only unfold under the pre-condition of severe inflammation.
5-4-2-5 Metalloproteinases and TGF-
The expression of TGF-1 and TGF-2, predominantly by
eosinophils, and their putative effects on fibroblast activity and
pathogenesis of nasal polyps have been suggested in several
studies (222-224). These studies compared protein levels in tissue
homogenates from patients with nasal polyps who were either
untreated or treated with oral corticosteroid, and control subjects. Patients with untreated polyp samples and controls
showed significantly higher concentrations of IL-5, eotaxin,
ECP and albumin, and significantly lower concentrations of
TGF-?1. In contrast, corticosteroid treatment significantly
reduced IL-5, ECP and albumin concentrations, whereas TGF1 was increased (205).
These observations suggest that IL-5 and TGF-1 represent
cytokines with counteracting activities, with a low TGF-1 protein concentration in IL-5 driven nasal polyps. Furthermore,
they support the deposition of albumin and other plasma proteins as a possible pathogenic principle of polyp formation,
caused by the lack of upregulation/production of TGF-1. The
lack of TGF also may prevent the upregulation of TIMPs, thus
failing to prevent ECM breakdown by metallo-proteinases. The
relative down-regulation of ECM is especially apparent in comparison to CRS, demonstrating a significantly increased TGF
versus controls (269).
TGF-1 is a potent fibrogenic cytokine that stimulates extracellular matrix formation, acts as a chemoattractant for fibroblasts,
but inhibits the synthesis of IL-5 and abrogates the survival-prolonging effect of haematopoietins (IL-5 and GM-CSF) on
eosinophils (225). Staphylococcal enterotoxins may induce a further
down-regulation of TGF in specific populations of patients (346).
Oedema and pseudocyst formation characterize NP, with a few
areas of fibrosis. An imbalance of metallo-proteinases with an
upregulation of MMP-7 and MMP-9, but not TIMP-1, in nasal
polyps has been recently demonstrated (408). This results in the
enhancement of MMP-9 in NP, which may account for oedema formation with albumin retention. The therapeutic effect
of macrolide antibiotics may partially be related to the suppression of MMPs in the airways (409).
Supplement 20
5-4-2-6 Nitric Oxide (NO)

Inducible nitric oxide synthase (iNOS) expression is upregulated in nasal polyp epithelium, especially in patients with asthma
and aspirinexacerbated respiratory disease (410). The role of
NO in nasal polyp formation and the possible diagnostic use
are currently evaluated.
5-4-3 Impact of Staphylococcus aureus enterotoxins (SAEs)
Early studies have shown that tissue IgE concentrations and
the number of IgE positive cells may be raised in nasal polyps,
suggesting the possibility of local IgE production (411). The local
production of IgE is a characteristic feature of nasal polyposis,
with a more than tenfold increase of IgE producing plasma
cells in NP versus controls. Analysis of specific IgE revealed a
multiclonal IgE response in nasal polyp tissue and IgE antibodies to Staphylococcus aureus enterotoxins (SAEs) in about 30-50%
of the patients and in about 60-80% of nasal polyp subjects
with asthma (192, 343, 348, 412-414). A recent prospective study revealed
that colonization of the middle meatus with Staphylococcus
aureus is significantly more frequent in NP (63.6%) compared to
CRS (27.3%, p< 0.05), and is related to the prevalence of IgE
antibodies to classical enterotoxins (27.8 vs 5.9%) (415). If aspirin
sensitivity, including asthma, accompanied nasal polyp disease,
the S. aureus colonization rate was as high as 87.5%, and IgE
antibodies to enterotoxins were found in 80% of cases.
Total and specific IgE as well as ECP in polyp homogenates
are only partially reflected in the serum of the patients, however, the likelyhood is clearly increased in patients with nasal
polyps and asthma. Staining of NP tissue revealed follicular
structures characterised by B- and T-cells, and lymphoid
agglomerates with diffuse plasma cell infiltration, demonstrating the organization of secondary lymphoid tissue with consecutive local IgE production in NP (416).
The classical SAEs, especially TSST-1 and Staphylococcus protein A (SPA), are excellent candidates to induce multiclonal
IgE synthesis by increasing the release of IL-4 as well as the
expression of CD40 ligand on T-cells and B7.2 on B-cells cells
cells (417, 418). SPA furthermore interacts with the VH3-family of
immunoglobulin heavy chain variable gene products and thus
preferentially selects plasma cells presenting such
immunoglobulins on their surface, which leads to a VH3 bias
(419)
. In fact, follicle-like aggregates can be found in nasal polyps,
expressing CD20+ B-cells, CD3+ T-cells and IgE plasma cells,
but largely lacking CD1a+ dendritic antigen presenting cells,
supporting the concept of a superantigen stimulation (416). SAEs
furthermore stimulate T-cells by binding to the variable betachain of the T-cell receptor, which induces cytokine production of IL-4 and IL-5, directly activate eosinophils and prolong
their survival and also may directly activate epithelial cells to
release chemokines (420). SAEs also activate antigen-presenting
cells to increase antigen uptake.
In vivo animal models support the pivotal role of SAEs in airway disease (421), with SAEs inducing eosinophilic inflammatory responses in sensitized mice in both, the upper and the
Table 5-7. Inflammatory mediatos (cytokines, chemokines, adhesion molecules, eicosanoids, and matrix metalloproteinases) in Chronic Rhinosinusitis
without nasal polyps (IHC: immunohistochemistry; RT-PCR: reverse-transcriptase protein chain reaction; ELISA: enzymo-linked immunosorbent
assay; CRS; chronic rhinosinusitis without nasal polyps; NP: chronic rhinosinusitis with nasal polyps; FESS: functional ensodcopic sinus surgery)
author, year
Camilos, 1993
(99)
Xaubet, 1994 (370)
Mullol, 1995 (427)
tissue, patient
nasal polyps
sinonasal mucosa (biopsies)
nasal polyps
sinonasal mucosa
marker
GM-CSF, IL-3
technique
IHC
GM-CSF
IHC
conclusion
cellular sources of GM-CSF and IL-3 in NP
remain to be determined
eosinophil infiltration into the respiratory
mucosa (allergic reaction, CRS with nasal
polyps) is modulated by epithelial cell GMCSF
nasal polyps
IL-8, GM-CSF, IL-1, ELISA
nasal polyps may represent a more active
sinonasal mucosa
IL-6, IL-8, TNF-
RT-PCR
Bartels, 1997 (376)
nasal polyps
sinonasal mucosat
CC-chemokines
eotaxin, RANTES
and MCP-3
ELISA
inflammatory tissue (more cytokines) than

expression of eotaxin and RANTES but no
MCP-3 is elevated in atopic and non-atopic
NP compared to normal mucosa
Bachert, 1997 (26)
nasal polyps
sinonasal mucosa
IL-1 , IL-3, IL-4,

ELISA
IL-5, IL-6, IL-8, IL-10,
IL-5 plays a key role in eosinophil

pathophysiology of nasal polyps and may
TNF-, GM-CSF,
IL-1RA, RANTES,
be produced by eosinophils.
GRO-
IL-4, IL-5, IFN-
mRNA
RT-PCR
Southern blot
Simon, 1997 (371)
nasal polyps
healthy sinonasal mucosa
allergic rhinitis mucosa
nasal polyps
IL-5
Bachert, 1998 (278)
nasal polyps
Th1, Th2 cytokines
ELISA
RT-PCR
Elispot
Bachert, 2001 (428)
nasal polyps
sinonasal mucosa
IL-5, IL-4, eotaxin,

ELISA
LTC4/D4/E4, sCD23, ImmunoCAP
histamine, ECP,
tryptase, total and
specific IgE for
allergens and
S. aureus enterotoxins
Gevaert, 2003 (375)
nasal polyps
sinonasal mucosa
Soluble IL-5R
RT-PCR
antagonistic soluble isoform is upregulated,

the signal transducing transmembrane
isoform is down-regulated in nasal polyps,
mainly in asthma.
Wallwork, 2004 (304)
CRS nasal mucosa

(in vivo & in vitro)
TGF-1, NFkB
IHC
clarythromycin inhibites TGF-1 and NFB

only in vitro
Watelet, 2004a
MMP-9, TGF-1
IHC
ELISA
correlation with the tissue healing quality
TGF-1
IHC
CRS without NP: increased expression of

TGF-1 compared to NP
CRS patients: increase of CCR4+ in atopics
and decrease of CCR5+ in non-atopics
different profile expression in CRS, NP,
Ming, 1997 (372)
(303)
Watelet, 2004b (408)
NP and allergic rhinitis may differ in the

mechanism by which IL-4 and IL-5 are
increased
IL-5 is an important cytokine that may
delay the death process in NP eosinophils
Th1 and Th2 type cytokines are
upregulated in NP, irrespective of allergen
skin test results.
association between increased levels of
total IgE, specific IgE, and eosinophilic
inflammation in NP
Elhini, 2005 (294)
ethmoidal sinus mucosa
CCR4+, CCR5+
Lu, 2005 (302)
sinonasal mucosa (surgery)
MMP-7, MMP-9,
ELISA
IHC
real time PCR
ELISA
Prez-Novo, 2005 (288)
sinonasal mucosa
Toppila-Salmi, 2005 (296)
real time PCR

ELISA
IHC
and healthy mucosa

CRS: COX-2 and PGE2 are more expressed
than in NP
increased expression in CRS endothelial cells
Lane, 2006 (429)
maxillary sinus mucosa

(surgery)
ethmoidal mucosa (surgery)
TIMP-1, TGF-1
COX-2
PGE2
L-selectin ligands
real time PCR
CRS: increase compared to healthy controls
Lee, 2006 (295)
sinonasal mucosa
increased expression of CCL20 in CR
Olze, 2006 (378)

Prez-Novo, 2006 (297)
nasal polyps
turbinate mucosa
nasal mucosa
eotaxin, eotaxin-2,
and -3
CysLT receptors
EP Receptors
IHC
real time PCRS
ELISA
real time PCR
CRS: CysLT and EP receptors are more

expressed than in NP
Rudack, 2006 (286)
sinonasal mucosa
Watelet, 2006 (306)
GRO-, GCP-2, IL-8,

ENA-78
MMP-9
TLR2, RANTES,
GM-CSF
CCL-20
eotaxin is expressed in CRS
HPLC + bioassay expression of GRO- and GCP-2 in CRS

IHC
correlation between MMP-9 expression and

tissue healing quality
32
lower airways, when applicated in either of those locations (422).

In fact, when comparing SAE-IgE positive nasal polyps to
SAE-IgE negative, the number of IgE positive cells and
eosinophils is significantly increased. The more severe inflammation is also reflected by significantly increased levels of IL-5,
ECP and total IgE. Furthermore, a possible link to aspirin sensitivity has been proposed, with SAEs creating a severe inflammation possibly serving as a basis for the specific changes seen
in aspirin sensitivity (412, 414). A review on the current knowledge
on the impact of SAEs on nasal polyp disease and lower airway
disease was recently published (206). IgE antibody formation to
SAE can be seen in nasal polyp tissue, but rarely in CRS without polyps.
In conclusion, SAEs are able to induce a more severe
eosinophilic inflammation as well as the synthesis of a multiclonal IgE response with high total IgE concentrations in the
tissue, which would suggest that SAEs are at least modifiers of
disease in CRS with nasal polyps (206, 420). Interestingly, similar
findings have recently been reported in asthma, which is
known to be associated with NP (349), and in COPD (423), thus
providing a link between upper and lower airways.
5-4-4 Nasal polyps in cystic fibrosis
NPs and CF-NPs share the remodelling pattern, i.e. they can
be discriminated from CRS without polyps and controls by the
oedema formation. Different to NPs, CF-NP display a very
prominent neutrophilic inflammation, with abnormally
increased concentrations of IL-1, IL-8 and MPO (269) and an
increased activity of NFkB (424), whereas macrophages, but not
eosinophils, are significantly increased over control mucosa.
Furthermore, there seems to be a reactive imbalance in innate
immunity markers, with mRNA expression of HBD 2 and of
TLR 2 being significantly higher in CF-NP compared to nonCF-NP (425).
The calcium-activated chloride channel hCLCA1 is thought to
regulate the expression of soluble gel-forming mucins, and is
upregulated by IL-9. Increased expression of IL-9 and IL-9R,
as well as upregulation of hCLCA1, in mucus-overproducing
epithelium of patients with cystic fibrosis supports the hypothesis that IL-9 contributes to mucus overproduction in cystic
fibrosis (426).
5-4-5 CRS with or without nasal polyps
When searching through the literature, it is apparent that definitions do matter; especially in older literature, the term CRS
was confused by hyperplastic CRS or hyperplastic CRS with
polyp formation, which would probably be equivalent to NPs
rather than CRS. However, because of a lack of clinical data
provided in those papers, the distinction between these diseases can often not be made, and the interpretation from those
studies has to be done with caution. For the purpose of this
chapter, we have used clearly defined patient populations.
Whereas NPs are characterized by oedema formation, with an
increased VPF/VEGF, an upregulation of MMPs, but not
Supplement 18
TIMP, and a low level or decrease in TGF-1, CRS shows a

fibrotic remodelling pattern with a balanced MMP system and
a significantly increased TGF- protein content (269). This fundamental difference has been linked to the predominant type
of inflammation: eosinophilic or neutrophilic; however, this
notion has to be challenged in the light of 1) the fact that NPs
and NPs in CF both show oedema formation, but are characterized by either abundant eosinophils or neutrophils and their
products; and 2) the fact that NPs from different parts of the
world do not show the same degree of eosinophilic inflammatory pattern (Zhang 2006). It is important to note that also in
NPs, the number of neutrophils is increased versus controls,
and the frequent impression of a predominantly eosinophilic
inflammation neglects those cells.
Both chronic sinus diseases, CRS and NPs, show increased
numbers and activation of T-cells, while only NPs display a
significant increase in plasma cells and consecutive
immunoglobulin synthesis (269). The role of this observation is
unclear, and may reflect a constant microbial trigger.
NP have significantly higher levels of eosinophilic markers
(eosinophils, eotaxin and ECP) compared to CRS and controls
in Caucasians, in whom CRS is characterized by proinflammatory cytokines (IL-1 and TNF-), a Th1 polarisation with high
levels of IFN-, and a significant increase in profibrotic TGF-,
while NPs show a Th2 polarisation with high IL-5 and IgE concentrations and a decrease in TGF- (269). Further studies will
have to investigate TH1 and TH2-specific transduction signals,
as well as the role of T regulatory cells, to fully understand the
stability of these patterns; studies in non-caucasian populations
may further be helpful to differentiate primary from secondary
phenomena.
5-5 Aspirin sensitivity Inflammatory mechanisms in acute and
chronic rhinosinusitis
5-5-1 Introduction
The presence of aspirin-intolerance in a patient with rhinosinusitis with or without nasal polyposis is associated with a particularly persistent and treatment-resistant form of disease,
coexisting usually with severe asthma and referred to as the
aspirin triad (430). The prevalence of nasal polyposis in aspirinsensitive asthmatics may be as high as 60-70%, as compared to
less than 10% in the population of aspirin-tolerant asthmatics
(34)
.The unusual severity of the upper airway disease in these
patients is reflected by high recurrence of nasal polyps, and frequent need for endoscopic sinus surgery (25, 431, 432). Rhinosinusitis
in aspirin hypersensitive patients with nasal polyposis is characterized by involvement of all sinuses and nasal passages and
higher thickness of hypertrophic mucosa as has been documented with computer tomography (433).
5-5-2 Mechanisms of acute ASA-induced reactions
In ASA-sensitive patients acute nasal symptoms (sneezing, rhinorrhea and congestion) may be induced by challenge with
33
oral or intranasal aspirin but also with other cross-reacting

nonsteroidal anti-inflammatory drugs (NSAIDs). The mechanism of these acute adverse reactions has been attributed to
inhibition by NSAIDs of an enzyme cyclooxygenase-1, with
subsequent inflammatory cell activation and release of both
lipid and non-lipid mediators (434, 435). The ASA-induced nasal
reaction is accompanied by an increase in both glandular
(lactoferrin, lysozyme) and plasma (albumin) proteins in nasal
secretions indicating a mixed response, involving both glandular and vascular sources (388). Concomitant release of both mast
cell (tryptase, histamine) and eosinophil (ECP) specific mediators into nasal washes clearly indicate activation of both types
of cells (436-438). Increased concentration of cysteinyl leukotrienes
in nasal secretion was also observed within minutes after ASAchallenge although the cellular source of leukotrienes has not
been determined (439). In parallel with inflammatory mediator
release an influx of leucocytes into nasal secretions occurred
with significant enrichment in eosinophils (436).
and survival or may act as a superantigen to trigger a T-cell

mediated inflammatory reaction (412).
5-5-3 Chronic rhinosinusitis with nasal polyps

Although the pathogenesis of chronic eosinophilic inflammation of the airway mucosa and nasal polyps in ASA-sensitive
patients, does not seem to be related to intake of aspirin or
other NSAIDs it has been speculated that the pathomechanism underlying rhinosinusitis with nasal polyps in aspirinsensitive patients may be different from that in aspirin tolerant
patients (440).
5-5-3-1 Cells and cytokine profile
A high degree of marked tissue eosinophilia is a prominent
feature of rhinosinusits with nasal polypos in ASA-hypersensitive patients and accordingly significantly more ECP was
released from non-stimulated or stimulated nasal polyp dispersed cells from ASA-sensitive patients (350, 441). An increased
number of eosinophils in the tissue has been linked to a distinctive profile of cytokine expression with upregulation of several cytokines related to eosinophil activation and survival (eg.
IL-5, GMC-SF, RANTES, eotaxin) (442-444). It has been suggested
that overproduction of IL-5 might be a major factor responsible for an increased survival of eosinophils in the nasal polyps
resulting in increased intensity of the eosinophilic inflammation particularly in aspirin-sensitive patients. In fact decreased
apoptosis was documented in polyps from aspirin-sensitive
patients, and increased infiltration with eosinophils was associated with prominent expression of CD45RO+ activated/memory cells and this cellular pattern was related to clinical features
of rhinosinusitis (445) Bachert at al (192) demonstrated that IgEantibodies to Staphylococcal enterotoxins (SAEs) were present
in nasal polyp tissue and their concentration correlated with
the levels of ECP, eotaxin and IL-5. These relations seemed to
be particularly evident in ASA-sensitive patients suggesting
that an increased expression of IL-5 and ECP in polyp tissue
from ASA-sensitive patients may be related to the presence of
SAE that can exert direct effects on eosinophil proliferation
Not only activated eosinophils but also mast cells are abundant
in the nasal polyps tissue from ASA-sensitive patients (355, 446).
The density of mast cells was correlated with the number of
polypectomies, implicating an important role for these cells in
the pathogenesis of CRS with nasal polyps. Stem cell factor
(SCF) also called c-kit ligand is a multi-potent cytokine generated by nasal polyp epithelial cells and critical for differentiation, survival, chemotaxis and activation and of human mast
cells but also involved in eosinophil activation and degranulation. SCF expression in nasal polyp epithelial cells in culture
correlated closely with the density of mast cells in nasal polyp
tissue and was significantly higher in asthmatic patients with
aspirin hypersensitivity as compared to aspirin tolerant patients
(355)
.
5-5-3-2 Arachidonic acid metabolites
Since Szczeklik et al (447) reported an increased susceptibility of
nasal polyps cells from ASA-sensitive patients to the inhibitory
action of aspirin, arachidonic aid metabolism abnormalities
have been considered a distinctive feature of nasal polyps in
this subpopulation of patients. A significantly lower generation
of PGE2 by nasal polyps and, nasal polyp epithelial cells as
well as a decreased expression of COX-2 in nasal polyps of
these patients were reported (398, 448). Low expression of COX-2
mRNA in nasal polyps from ASA-sensitive patients was in turn
linked to a downregulation of NF-B activity and to abnormal
regulation of COX-2 expression mechanisms at the transcriptional level (449, 450). Since PGE2 has significant anti-inflammatory
activity, including inhibitory effect on eosinophil chemotaxis
and activation, it has been speculated that an intrinsic defect in
local generation of PGE2 could contribute to development of
more severe eosinophilic inflammation in aspirin-sensitive
patients. Although a significant deficit of PGE2 was demonstrated in polyp tissue of ASA-sensitive as compared to ASAtolerant patients, decreased expression of COX-2mRNA and
PGE production seem to be a feature of CRS with nasal polyps
also in patients without ASA-sensitivity representing more
general mechanism involved in the growth of nasal polyps. On
the other hand the percentages of neutrophils, mast cells,
eosinophils, and T cells expressing prostaglandin EP2, but not
EP1, EP3, or inflammation in ASA-sensitive patients and some
studies demonstrated an increased production of cysteinyl
leukotrienes in nasal polyps of ASA-sensitive asthmatics as
compared to aspirin tolerant patients in vitro (400, 451) but these
observations could not be reproduced in vivo when nasal
washes were analysed (388, 452). Similarly when nasal polyp dispersed cells were cultured basal and stimulated release of
LTC4 was found to be similar in nasal polyp cells from from
ASA-sensitive and ASA-tolerant patients (355). Whole blood
cells from aspirin sensitive and tolerant patients did not differ
in their ability to generate cyclooygenase and lipoxygenase
34
products (453) . More recently an increased expression of

enzymes involved in production of leukotrienes (5-LOX and
LTC4 synthase) and an increased generation of LTC4/D4/E4
in nasal polyp tissue from ASA-sensitive patients were found
(288, 439, 454)
. Cysteinyl leukotriene production correlated with tissue
ECP concentration both in ASA-sensitive and ASA-tolerant
polyps suggesting that these mediators may be linked to tissue
eosinophilia rather that to aspirin-sensitivity. On the other
hand an increased expression of leukotriene LT1 receptors was
found in the nasal mucosa of ASA-sensitive patients, suggesting local hyper-responsiveness to leukotrienes in this subpopulation of patients (389, 392). More recently other arachidonic acid
metabolites generated on 15-LOX pathway have been associated with CRS with nasal polyps in ASA-sensitive patients. In
nasal polyp epithelial cells from ASA-sensitive but not ASA-
Supplement 20
tolerant patients aspirin triggers 15-HETE generation, suggesting the presence of a specific abnormality of 15-LO pathway in
these patients (448). Upregulation of 15-lipoxygenase and
decreased production of the anti-inflammatory 15-LO metabolite lipoxin A4 found in nasal polyp tissue from ASA-sensitive
patients further points to a distinctive but not yet understood
role for 15-LO metabolites in nasal polyps (288).
5-6 Conclusion
Although far from being completely understood, pathomechanisms in ARS, CRS and NP are better understood today and
begin to allow us to differentiate these diseases via their
cytokine profile, their pattern of inflammation as well as
remodeling processes.
35
6. Diagnosis
6-1 Assessment of rhinosinusitis symptoms
6-1-1 Symptoms of rhinosinusitis

Subjective assessment of rhinosinusitis is based on symptoms.
nasal blockage, congestion or stuffiness;
nasal discharge or postnasal drip, often mucopurulent;
facial pain or pressure, headache, and
reduction/loss of smell.
Besides these local symptoms, there are distant and general
symptoms. Distant symptoms are pharyngeal, laryngeal and
tracheal irritation causing sore throat, dysphonia and cough,
whereas general symptoms include drowsiness, malaise and
fever. Individual variations of these general symptom patterns
are many (24, 455-459). It is interesting to note that only a small proportion of patients with purulent rhinosinusitis, without coexisting chest disease, complain of cough (460).
The symptoms are principally the same in acute and chronic

rhinosinusitis as well as in CRS with nasal polyps, but the
symptom pattern and intensity may vary. Acute forms of infections, both acute and acute exacerbations of chronic rhinosinusitis, have usually more distinct and often more severe
symptoms.
Simple nasal polyps may cause constant non-periodic nasal
blockage , which can have a valve-like sensation allowing better airflow in only one direction. Nasal polyps may cause nasal
congestion, which can be a feeling of pressure and fullness in
the nose and paranasal cavities. This is typical for ethmoidal
polyposis, which in severe cases can cause widening of the
nasal and paranasal cavities demonstrated radiologically and in
extreme cases, hyperteliorism. Disorders of smell are more
prevalent in patients with nasal polyps than in other chronic
rhinosinusitis patients (25).
6-1-2 Subjective assessment of the symptoms
Subjective assessment of the symptoms should consider the
strength or degree of the symptoms, the duration of the symptom. During the last decade more attention has been paid not
only to symptoms but also to their effect on the patients quality of life (QoL) (461, 462).
The assessment of subjective symptoms is done using questionnaires or in clinical studies recorded in logbooks.
Evaluation frequency depends on the aims of the study, usually once or twice daily. Continuous recording devices are also
available.
The degree or strength of the symptoms can be estimated
using many different grading tools.
recorded as such: severe, moderate, slight and no symptom;
recorded as numbers: from 0 to 4 or as many degrees as

needed;
recorded as VAS score on a line giving a measurable continuum (0 10 cm).
Terms such as mild, moderate or severe may include both

symptom severity estimation, but also an estimate of duration
i.e. moderate symptom severity can mean an intense symptom but only for a short time in the recorded period or less
severe symptom but lasting for most of the recording period.
A recent study has considered the relationship between subjective assessment instruments in chronic rhinosinusitis and has
shown that mild equates to a visual analogue score of 3 or
less, moderate to >3-7 and severe to >7-10(14).
The duration of the symptoms is evaluated as symptomatic or
symptom-free moments in given time periods, i.e. as hours
during the recording period or as day per week.
No symptom can be regarded as a consistent finding in most
studies. It provides the possibility to record time periods (eg.
days) without symptoms, which can be reliably compared
between testees (inter-patient) and from study to study.
These criteria are inconsistent and not always comparable
when considering rhinosinusitis. (459), where the symptoms may
fluctuate from time to time. Nevertheless in many randomised,
controlled and prospective rhinosinusitis intervention studies,
both allergic and infective, these methods of recording symptoms have given statistically significant results.
In a study correlating nasosinal symptoms with topographic
distribution of chronic rhinosinuitis as demonstrated by CT
scanning, the symptoms of nasal obstruction, anterior and
posterior nasal discharge, sneezing and facial congestion
failed to discriminate site of disease. By contrast loss of smell
and flavour were correlated with what the authors refer to as
diffuse rhinosinusitis ie mainly CRS with nasal polyps,
whereas cacosmia and facial pain correlated with localised or
anterior sinusitis ie mainly sinusitis of dental or foreign body
origin. (84)
6-1-3 Validation of subjective symptoms assessment
Validation of the rhinosinusitis symptoms to show the relevance in distinguishing disease modalities and repeatabilty
between ratings of the same patient (intrapatient, longitudinal
validity) and between different patients (interpatient, cross-sectional validity) have been done. Lately, more specific and validated subjective symptom scoring tools have become available
36
with the development of quality of life (QoL) evaluations.

These are either assess general health evaluating (463, 464) or are
disease specific (461, 462, 465).
6-1-3-1 Nasal obstruction
Validation of subjective assessment of nasal obstruction or
stuffiness has been done by studying the relationship between
subjective and objective evaluation methods for functional
nasal obstruction. However, the patients interpretation of
nasal blockage varies from true mechanical obstruction of airflow to the sensation of fullness in the midface.
Generally the subjective sensation of nasal obstruction and rhinomanometric or nasal peak flow evaluations show a good
intra-individual correlation in a number of studies considering
normal controls, patients with structural abnormalities, hyperreactivity or infective rhinitis (466-470). However, there are also
some studies where this correlation is not seen (471) or the correlation was poor (472, 473).
The interpatient variation in subjective scoring suggests that
every nose is individually calibrated, which makes interpatient comparisons less reliable but still significant (466, 468).
Subjective nasal obstruction correlates better with objective
functional measurements of nasal airflow resistance (rinomanometry, peak flow) than with measurements of nasal cavity width, such as acoustic rhinometry (470, 474).
Nasal obstruction can also be assessed objectively by tests
using personal nasal peak flow instruments, inspiratory or expiratory, which patients can take home or to their work place and
do measurements at any desired time intervals.
Subjective assessment of nasal obstruction is a well validated
criterion.
6-1-3-2 Nasal discharge
Techniques for objective assessment of nasal discharge are not
as good as for nasal obstruction: Counting the nose blowings
in a diary card or using a new handkerchief from a counted
reservoir for each blow and possibly collecting the used handkerchieves in plastic bags for weighing have been used in acute
infective rhinitis (475) and in autonomic (previously termed
vasomotor) rhinitis (476).
Validating correlation studies between objective discharge
measures (collecting and measuring amount or weight of nasal
secretion as drops, by suction, or using hygroscopic paper
strips etc) and subjective scoring of nasal discharge or postnasal drip has not been done.
6-1-3-3 Smell abnormalities
Fluctuations in the sense of smell are associated with chronic
rhinosinusitis. This may be due to mucosal obstruction of the
olfactory niche (conductive loss) and/or degenerative alter-
Supplement 20
ations in the olfactory mucosa due to the disease or its treatment eg repeated nasal surgery.
Subjective scoring of olfaction is a commonly used assessment
method. In validating clinical settings, subjective scores have
been found to correlate significantly to objective olfactory
threshold and qualitative tests in normal population, rhinosinusitis and other disease conditions (477-480) as well as numerous
clinical studies concerning other diseases than rhinosinusitis
(Evidence level Ib).
6-1-3-4 Facial pain and pressure
Facial or dental pain, especially unilateral, have been found to
be predictors of acute maxillary sinusitis with fluid retention in
patients with a suspicion of infection, when validated by maxillary antral aspiration (455) or paranasal sinus radiographs (481). The
importance of facial pain as a cardinal sign of chronic rhinosinusitis has also been called into question (482) where the symptoms are more diffuse and fluctuate rendering the clinical correlation of facial pain and pressure scorings against objective
assessments unconvincing. Poor correlation between facial
pain localisation and the affected paranasal sinus CT pathology
in patients with supposed infection, both acute and chronic,
has been reported (483). However, rhinosinusitis disease specific
quality of life studies also include facial pain-related parameters, which have been validated (465).
6-1-3-5 Overall rating of rhinosinusitis severity
Overall rating of rhinosinusitis severity can be obtained as such
or by total symptoms scores, which are summed scores of the
individual symptoms scores. These are both commonly used,
but according to an old validation study for measuring the
severity of rhinitis, scores indicating the course of individual
symptoms should not be combined into a summed score,
rather the patient's overall rating of the condition should be
used (484). QoL methods have produced validated questionnaires
which measure the impact of overall rhinosinusitis symptoms
on everyday life (461).
6-1-3-6 Chronic Sinusitis Survey (CSS)
This is a 6 item duration based monitor of sinusitis specific
outcomes which has both systemic and medication-based sections (485). In common with other questionnaires, it is rather better at determining the relative impact of chronic rhinosinusitis
compared to other diseases than as a measure of improvement
following therapeutic intervention but can be a useful tool (462,
486)
[Evidence Level IIb]. Mean scores one year after endoscopic
frontal sinus surgery showed a significant improvement in
symptoms of pain, congestion, and drainage and medication
use was also significantly reduced (487).
6-1-3-7 The Chronic Rhinosinusitis Type Specific Questionnaire
This test contains three forms. Form 1 collects data on nasal
and sinus symptoms prior to treatment, Form 2 collects data
37
interventions eg at 3, 6, 9 and 12 months. This has a high interrater concordance (489). A number of staging systems for polyps
have been proposed (490-492). Johansson showed good correlation
between a 0 3 scoring system and their own system in which
they estimated the percentage projection of polyps from the
lateral wall and the percentage of the nasal cavity volume occupied by polyps. However, they did not find a correlation
between size of polyps and symptoms. (Level III).
Table 6-1. Endoscopic appearances scores

characteristic
polyp left (0,1,2,3)
polyp, right (0,1,2,3)
oedema, left (0,1,2,)
oedema, right (0,1,2,)
discharge, left (0,1,2)
discharge, right (0,1,2)
postoperative scores to be used for
outcome assessment only
scarring, left (0.1,2)
scarring, right (0.1,2)
crusting, left (0,1,2)
crusting, right (0,1,2)
total points
Baseline & Follow-up
6-2-3 Nasal cytology, biopsy and bacteriology

Generally cytology has not proved a useful tool in diagnosis of
rhinosinusitis although a biopsy may be indicated to exclude
more sinister and severe conditions such as neoplasia and the
vasculitides.
0-Absence of polyps;
1-polyps in middle meatus only;
2-polyps beyond middle meatus but not blocking the nose completely;
3-polyps completely obstructing the nose.
Oedema: 0-absent; 1-mild; 2-severe.
Discharge: 0-no discharge; 1-clear, thin discharge; 2-thick, purulent
discharge.
Scarring: 0-absent; 1-mild; 2-severe.
Crusting: 0-absent; 1-mild; 2-severe.
Several microbiology studies (494-498) [Evidence Level IIb] have

shown a reasonable correlation between specimens taken from
the middle meatus under endoscopic control and proof puncture leading to the possibility of microbiological confirmation
of both the pathogen and its response to therapy (Table 6-2). A
meta-analysis showed an accuracy of 87% with a lower end
confidence level of 81.3% for the endoscopically directed middle meatal culture when compared with maxillary sinus taps in
acute maxillary sinus infection (499).
on the clinical classification of sinus disease and Form 3 data

on nasal and sinus symptoms after sinus surgery. Hoffman et
al have used this in combination with an SF-36 to look at
patient outcomes after surgical management of chronic rhinosinusitis though it is somewhat time consuming to complete (488).
6-2-4 Imaging
Plain sinus x-rays are insensitive and of limited usefulness for
the diagnosis of rhinosinusitis due to the number of false positive and negative results (501-503). Nevertheless it can be usefull to
prove ARS in studies.
6-2 Examination
Transillumination was advocated in the 1970 as an inexpensive

and efficacious screening modality for sinus pathology (504). The
insensitivity and unspecificity makes it unreliable for the diagnosis of rhinosinusitis (505).
6-2-1 Anterior rhinoscopy

Anterior rhinoscopy alone is inadequate, but remains the first
step in examining a patient with these diseases.
6-2-2 Endoscopy
This may be performed without and with decongestion and
semi-quantitative scores (457) for polyps, oedema, discharge,
crusting and scarring (post-operatively) can be obtained (Table
6.1) at baseline and at regular intervals following therapeutic
Sinus ultrasound is also insensitive and of limited usefulness

for the diagnosis of rhinosinusitis due to the number of false
positive and negative results. However, the results in well
trained hands are comparable to X-ray in the diagnostics of
ARS (41, 506, 507)
Table 6-2. Bacteriology of Rhinosinusitis; Correlation of middle meatus versus maxillary sinus
author
no of samples
type of rhinosinusitis
technique
concordance
Gold & Tami, 1997 (495)
21
chronic
endoscopic tap (MM) v maxillary aspiration during ESS
85.7%
Klossek et al, 1998 (494)
65
chronic
endoscoic swab (MM) v maxillary aspiration during ESS
73.8%
Vogan et al, 2000 (496)
16
acute
endoscoic swab (MM) v maxillary sinus tap
93%
Casiano et al, 2001
29
acute (intensive care)
endoscopic tissue culture (MM) v maxillary sinus tap
60%
Talbot et al, 2001 (500)
46
acute
endoscopic swab (MM) v maxillary sinus tap
90.6%
Joniau et al 2005
26
acute
endoscopic swab (MM) v

maxillary sinus tap
88.5%
(497)
(498)
MM: middle meatus; ESS: endoscopic sinus surgery
38
Supplement 20
CT scanning is the imaging modality of choice confirming the

extent of pathology and the anatomy. However, it should not
be regarded as the primary step in the diagnosis of the condition, except where there are unilateral signs and symptoms or
other sinister signs, but rather corroborates history and endoscopic examination after failure of medical therapy. The
demonstration of the complex sinonasal anatomy has been
regarded as at least as important as confirmation of inflammatory change(508-510). Considerable ethnic as well as individual differences may be encountered (511). Many protocols have been
described and interest has recently centred on improving definition whilst reducing radiation dose (512).
MRI is not the primary imaging modality in chronic rhinosinusitis and is usually reserved in combination with CT for the
investigation of more serious conditions such as neoplasia.
A range of staging systems based on CT scanning have been
described using stages 0-4 and of varying complexity (59, 490, 513-517).
The Lund-Mackay system relies on a score of 0-2 dependent
upon the absence, partial or complete opacification of each
sinus system and of the ostiomeatal complex, deriving a maximum score of 12 per side (Table 3) (490).
Table 6-3. CT scoring system (490)
sinus system
left
right
maxillary (0,1,2)
anterior ethmoids (0,1,2)
posterior ethmoids (0,1,2)
sphenoid (0,1,2)
frontal (0,1,2)
ostiomeatal complex
(0 or 2 only)*
It should be noted that incidental abnormalities are found on

scanning in up to a fifth of the normal population (64). A mean
LM score of 4.26 in adults (524) and 2.81 in children aged 1-18
years (525) have been reported. In addition for ethical reasons a
CT scan is generally only performed post-operatively when
there are persistent problems and therefore CT staging or scoring can only be considered as an inclusion criterion for studies
and not as an outcome assessment.
6-2-5 Mucociliary function
6-2-5-1 Nasomucociliary clearance
The use of saccharin, dye or radioactive particles to measure
mucociliary transit time has been available for nearly thirty
years (526-528). It allows if altered one to recognize early alterations
of rhinosinusal homeostasis Although a crude measure, it has
the advantage of considering the entire mucociliary system and
is useful if normal (<35 minutes). However, if it is prolonged,
it does not distinguish between primary or secondary causes of
ciliary dysfunction.
Nasomucociliary clearance has also been measured using a
mixture of vegetable charcoal powder and 3% saccharin to
demonstrate a delay in patients with CRS as compared to normals, hypertrophied inferior turbinates and septal deviation (529).
6-2-5-2 Ciliary beat frequency
Specific measurements of ciliary activity using a phase contrast
microscope with photometric cell (530, 531) have been used in a
number of studies to evaluate therapeutic success (532, 533)
[Evidence Level IIb]. The normal range from the inferior
turbinate is over 8 Hz but these techniques are available in
only a few centres to which children suspected of primary ciliary dyskinesia (PCD) should be referred. The final gold standard of ciliary function involves culture techniques for 6 weeks
(534)
.
total points
0-no abnormalities; 1-partial opacification; 2-total opacification.
*0-not occluded; 2-occluded
6-2-5-3 Electron microscopy

This may be used to confirm the presence of specific inherited
disorders of the cilia as in PCD.
This has been validated in several studies (518) [Evidence Level

IIb] and was adopted by the Rhinosinusitis Task Force
Committee of the American Academy of Otolaryngology Head
and Neck Surgery in 1996 (5). CT and endoscopic scores correlate well (519) but the correlation between CT findings and
symptom scores has generally been shown to be poor and is
not a good indicator of outcome (133, 520, 521) [Evidence Level IIb].
However, Wabnitz and colleagues did find a correlation
between VAS and CT score though not between CT score and
QoL as measured with the Chronic Sinusitis Score (522) .
Bhattacharyya compared three staging systems with the
Rhinosinusitis Symptom Inventory (523) and found the Lund
score to correlate best with nasal scores but the degree of correlation remained low.
6-2-5-4 Nitric oxide

This metabolite found in the upper and lower respiratory tract
is a sensitive indicator of the presence of inflammation and ciliary dysfunction, being high with inflammation and low in ciliary dyskinesia It requires little patient co-operation and is
quick and easy to perform using chemiluminescence, but the
availability of measuring equipment at present limits its use.
The majority of nitric oxide is made in the sinuses (chest < 20
ppb, nose 400-900 ppb, sinuses 20 25 ppm) using an LR 2000
Logan Sinclair nitric oxide gas analyser (values may differ with
different machines). Less than 100ppb from the upper and
<10ppb from the lower respiratory tract would be highly suspicious of PCD. However, whilst very low levels in the nose can
indicate primary ciliary dyskinesia, they may also be due to sig-
39
nificant sinus obstruction eg severe CRS with nasal polyps.

Conversely elevated levels suggest nasal inflammation but
ostiomeatal patency (535) [Evidence Level IIb]. It can potentially
be used, as an outcome measure after therapy (536) [Evidence
Level IIa] However, some contradictory results on the role of
nNO on nasal inflammation have been recently assessed (311).
encapsulated odorants are available (548) and have been utilised

in studies of both chronic rhinosinusitis with and without nasal
polyps (538). A cruder screening test, the Zurich Smell Diskette
test may also be used and has the advantage of pictorial representation of the items (549, 550). Also on a national footing, the
Barcelona Smell Test has been developed, comprising 24 odorants and has been compared with the Zurich Smell Diskette
Test (480). More complex tests exist (551) e.g. Sniff n sticks
which limit their application to the research setting. A combined supra-threshold detection and identification test has
been devised as a cross-cultural tool in the European population, the results of which are presented in the appendix (552)
[Evidence Level III].
6-2-6 Nasal airway assessment

6-2-6-1 Nasal inspiratory peak flow
This inexpensive, quick and easy test is a useful estimate of
airflow which can be performed at home as well as in the hospital setting. However, it measures both sides together and has
little direct role in the assessment of chronic rhinosinusitis. It
could be used to assess gross reduction in nasal polyps and
compares well with rhinomanometry (537, 538) [Evidence Level
IIb]. Normative data is now available in an adult Caucasian
population (539). Expiratory peak flow is less often used as
mucus is expelled into the mask and the technique may be
associated with eustachian dysfunction.
Furthemore in non-allergic, non-infectitious perennial rhinitis
versus controls, repeated PNIF resulted in a brief but statistically significant increase in nasal airway resistance in the
rhinitic patients suggesting a neuronal mechanism (540)
6-2-6-2 Rhinomanometry (active anterior and posterior).
The measurement of nasal airway resistance by assessing nasal
flow at a constant pressure is again of limited usefulness in
chronic rhinosinusitis and with and without nasal polyps but can
be useful in confirming that improvement in nasal congestion is
the result of reduction in inflammation in the middle meatus
rather than mechanical obstruction (532) [Evidence Level IIb].
6-2-6-3 Acoustic rhinometry
The distortion of a sound wave by nasal topography allows
quantification of area at fixed points in the nose from which
volume may be derived. It can be used to demonstrate subtle
changes, both as a result of medical and surgical intervention
(536, 538, 541, 542)
[Evidence Level IIa].
6-2-6-4 Rhinostereometry
This also measures subtle changes in mucosal swelling, largely
in the inferior turbinates (543, 544) [Level IIb] and is therefore not
directly applicable to assessment of chronic rhinosinusitis.
6-2-7 Olfaction
6-2-7-1 Threshold Testing
The estimation of olfactory thresholds by the presentation of
serial dilutions of pure odourants such as pm carbinol have been
used in a number of studies (533, 541, 545-547) [Evidence Level IIb].
6-2-7-2 Other quantitative olfactory testing
Scratch and sniff test using patches impregnated with micro-
Sources of some commercially available and validated olfactory tests are also mentioned in the appendix.
6-2-8 Aspirin and other challenges
Objective experiments to differentiate patient groups according
to rhinosinusitis severity or aetiology have been done using
nasal provocation with histamine or metacholine (553, 554) which
test mucosal hyper-reactivity. The tests can differentiate subpopulations with statistical significance, but because of considerable overlap of results, these tests have not achieved the
equivalent position in rhinitis severity evaluations as the corresponding bronchial tests i.e in asthma diagnosis.
Establishing a diagnosis of aspirin hypersensitivity is important
since it provides the patient with a long list of common drugs
that must not be taken in view of the risk of a severe reaction. It
diagnoses a particular type of asthma and sinonasal disease and
allows choice of a specific therapy, i.e. aspirin desensitization.
The oral aspirin challenge test was introduced to clinical practice in the early 1970s (555). Over the following years it was validated and more frequently used (556-558). An inhalation test was
introduced in 1977 by S Bianco. This challenge is safer and
faster to perform than the oral one, although less sensitive.( (559561)
. Contrary to the oral challenge it does not produce systemic
reactions. The nasal provocation test was employed in the late
1980s (562, 563). It is recommended especially for patients with predominantly nasal symptoms and those in whom oral or
inhaled tests are contraindicated because of the asthma severity. A negative nasal challenge should be followed by oral challenge. Lysine aspirin, the only truly soluble form of aspirin
must be used for both respiratory routes. Test procedures have
recently been reviewed in detail (564). The sensitivity and specificity of the tests are shown in Table 6-4.
Table 6-4. Diagnosis of aspirin sensitivity
history
challenge sensitivity (%)
specificity (%)
oral
77
93
bronchial
77
93
nasal
73
94
40
6-2-9 Laboratory assesments C-reactive protein (CRP)

Known since 1930, C-reactive protein is part of the acute phase
response proteins. Its principal properties are short half-life (68 h), rapid response (within 6 hours) and high levels (x500 normal) after injury. It activates the classical complement pathway,
leading to bacterial opsonization. Studies have shown that the
CRP value is useful in the diagnosis of bacterial infections (565).
However, among patients suspected of an infectious disease,
CRP levels up to 100 mg/l are compatible with all types of
infections (bacterial, viral, fungal, and protozoal) (566).
Sequential CRP measurements will have greater diagnostic
value than a single measurement and changes of the CRP values often reflect the clinical course. When used in general
practice the diagnostic value of CRP is found to be high in
adults with pneumonia, sinusitis and tonsillitis. Measurement
of CRP is an important diagnostic test but the analysis should
not stand alone but be evaluated together with the patient's
history and clinical examination (567).
CRP is most reliably used for exclusion of bacterial infection:
two values less than 10 mg/l and 8 12 hours apart can be taken
to exclude bacterial infection. (566).
6-3 Quality of Life
During the last decade more attention has been paid to not
only symptoms but also to patients quality of life (QoL) (462)
or more accurately health-related quality of life (HRQoL). The
QoL questionnaires can provide either general (generic) or disease specific health assessment. However, it is of interest that
the severity of nasal symptoms or findings do not always correlate with QoL scales (522, 568). [Evidence Level IIb].
6-3-1 General (generic) health status instruments
General (generic) measurements enable the comparison of
patients suffering from chronic rhinosinusitis with other
patient groups. Of these the Medical Outcomes Study Short
Form 36 (SF36) (463) is by far the most widely used and well validated and this has been used both pre- and post-operatively in
chronic rhinosinusitis. (536, 569) [Evidence Level IIa,IIb]. It
includes eight domains: physical functioning, role functioning
physical, bodily pain, general health, vitality, social functioning, role-functioning emotional and mental health. Many other
generic measurements are also available (464). For example
EuroQOL, Short Form-12 and Quality of Well-Being Scale
have been used in sinusitis studies (570).
The Glasgow Benefit Inventory has also been applied to
chronic rhinosinusitis and its treatment (571) as has the EuroQol
and McGill pain questionnaires (572, 573).
6-3-2 Disease specific health status instruments (see also appendix)
Several disease specific questionnaires for evaluation of quality
of life in chronic rhinosinusitis have been published. In these
questionnaires specific symptoms for rhinosinusitis are includ-
Supplement 20
ed. Such areas include headache, facial pain or pressure, nasal

discharge or postnasal drip, and nasal congestion. Disease specific questionnaires are usually used to measure effects within
the disease in response to interventions. They are usually more
sensitive than general health status instruments.
6-3-2-1 Rhinosinusitis outcome measure (RSOM) and
Sinonasal Outcome Test-20
RSOM contains 31 items classified into 7 domains and takes
approximately 20 minutes to complete (574). RSOM has been wellvalidated and allows measurement of symptom severity and
importance to the patient. The severity and importance scales,
however, make it somewhat difficult for the patient to fill the
questionnaire (575) RSOM-31 has been used in medical studies (576).
6-3-2-2 Sinonasal Outcome Test 20
A modified instrument referred to as the Sinonasal Outcome
Test 20 (SNOT 20) is validated and easy to use (465). This has been
used in a number of studies both medical and surgical (536, 577)
[Evidence Levels Ib, IIb]. However, the lack of the SNOT-20 is
that it does no contain questions on nasal obstruction and loss of
smell and taste. These questions are included in the SNOT-22
questionnaire which however is not validated. This test was the
primary outcome in the largest audit to date of surgery for chronic rhinosinusitis with or without nasal polyps (520).
6-3-2-3 Sinonasal Outcome Test 16
The Sinonasal Outcome Test 16 (SNOT 16) is also a rhinosinusitis specific quality of life health related instrument (578).
6-3-2-4 Rhinosinusitis Disablity Index (RSDI)
In this 30 item validated questionnaire, the patient is asked to
relate nasal and sinus symptoms to specific limitations on daily
functioning (461, 579). It is similar to the RSOM 31 in the types of
questions it contains. It can be completed easily and quickly
but does not allow the patient to indicate their most important
symptoms. However, it does have some general questions
similar to the SF-36.
6-3-2-5 Rhinoconjunctivitis quality of life questionnaire (RQLQ)
This is a well-validated questionnaire but specifically focuses
on allergy and is not validated in acute and CRS with or without NP (580).
A newer standardized version RQLQ(S) is also available and it
has been used for example in a nasal lavage study in chronic
rinosinusitis (581).
6-3-2-6 RhinoQOL
The RhinoQol is a sinusitis specific instrument which measures symptom frequency, bothersomeness and impact. It can
be used for acute and chronic sinusitis (582).
6-3-2-7 Rhinitis Symptom Utility Index (RSUI)
This consists of ten questions on the severity and frequency of
41
a stuffy or blocked nose, runny nose, sneezing, itching, watery

eyes and itching nose or throat. The RSUI is designed for costeffectiveness studies. The two-week reproducibility of the
RSUI was weak, probably reflecting the day to day variability
of rhinitis (583).
tionnaires demonstrated improvement in most domains when

post-opertaive results at 1 and 2 years were compared with
baseline (573).
6-3-2-8 SN-5
SN-5 is a validated HRQoL instrument that can be used to
measure childs QoL in relation to chronic sinonasal symptoms
(584, 585)
. The SN-5 domains are sinus infection, nasal obstruction, allergy symptoms, emotional distress, and activity limitations. The information for the questionnaire is given by a
childs caregiver.
6-3-3-2 Disease specific questionnaires

A disease-specific questionnaire seems to be more sensitive
than a general questionnaire in following patients after ethmoid sinus surgery (485). 76% patients reported relief of the
symptoms at least in two of the domains studied after FESS
surgery (459).
Despite similarities in objective disease measures, female
patients reported significantly worse QoL scores before and
after FESS surgery as measured with RSDI questionnaire (590).
6-3-3 Results
6-3-3-1 General (generic) questionnaires
In three generic SF-36 surveys the scores of chronic rhinosinusitis patients were compared to those of a healthy population. The results showed statistically significant differences in
seven of eight domains (572, 586, 587). Two studies have reported that
patients with chronic rhinosinusitis have more bodily pain and
worse social functioning than for example patients with chronic obstructive pulmonary disease, congestive heart failure, diabetes, or back pain (572, 588).
The EuroQol, SF-36 and McGill pain questionnaire were used
to assess 56 patients with refractory CRS in an RCT investigating use of filgrastim. Baseline results confirmed that patient
QOL was below normal and suggested an improvement
(though not significant) in the actively treated group (572).
The effect of surgical treatment was studied with generic questionnaires preoperatively and usually 3, 6 or 12 months after
the operation (512, 573, 587). Following endoscopic sinus surgery, the
SF-36 questionnaire demonstrated a return to normality in all
eight domains six months post-operatively which was maintained at twelve months (569). In a study by Gliklich and Metson
after the sinus surgery significant improvements were found in
reduction of the symptoms and medications needed (486).
Significant improvements in general health status were noted
in six of eight categories, and most attained near-normative
levels. Oral steroid treatment also had a similar effect on
HRQoL as surgery as measured by SF-36 (587).
Radenne et al. have studied the QoL of nasal polyposis
patients using a generic SF-36 questionnaire (568). Polyposis
impaired the QoL more than for example perennial rhinitis.
Treatment significantly improved the symptoms and the QoL
of the polyposis patients. FESS surgery on asthmatic patients
with massive nasal polyposis improved nasal breathing and
QoL, and also the use of asthma medications was significantly
reduced (589).
In a recent study evaluating the effect of radical surgery on
QoL, the SF36 and McGill Pain questionnaires were used on
23 patients who underwent Denkers procedures. Both ques-
The RSOM questionnaire was used in a study where the effect

50 mg prednisolone or placebo daily for 14 days was compared
(576)
. Significant improvement was noted in total RSOM score
with both active and placebo treatments (53% vs. 21%).
However, the subset of nasal-spesific RSOM scores (6 parameters) showed significant improvement only in the prednisolone
group.
In a recent randomised study of patients with chronic rhinosinusitis/nasal polyposis, treatment was either endoscopic sinus
surgery or three months of a macrolide antibiotic such as erythromycin (536). Patients were followed up at 3, 6, 9 and 12
months with a variety of parameters including visual analogue
scores of nasal symptoms, SNOT 20, SF-36, nitric oxide measurements of upper and lower respiratory tract expired air,
acoustic rhinometry, saccharine clearance test and nasal
endoscopy. Ninety patients were randomised, with 45 in each
arm and at the end of one year, 38 were available for analysis
in the medical arm and 40 in the surgical arm. The study
showed that there had been improvement in all subjective and
objective parameters (p <0.01) but there was no difference
between the medical and surgical groups except that total nasal
volume as measured by acoustic rhinometry was greater in the
surgical group. This study shows the usefulness of objective
measurement in confirming subjective impressions (Evidence
Level 1b).
In a prospective multicentre cohort study of 3128 adults undergoing surgery for chronic rhinosinusitis/nasal polyposis healthrelated quality of life was compared at 12 and 36 months after
surgery using a SNOT-22 questionnaire. This is a non-validated modification of the SNOT-20 by the addition of two questions on nasal blockage and sense of taste and smell and was
useful in demonstrating significant improvement following
surgery which did not change between 12 and 36 months (520).
However, it was not possible with this outcome measure to
show advantage of extended sinus clearance over simple
polypectomy.
42
Nowadays there are many generic and disease specific HRQoL

questionnaires available to rhinosinusitis studies. However,
most of the questionnaires are not yet validated. QoL measurement is quite a new tool evaluating the impact of disease and
the efficacy of treatment. In rhinosinusitis studies, when the
effect of medical treatment or surgery has been evaluated, QoL
has been considered to be an important outcome measurement as distinct from classic rhinosinusitis symptom parameters. In a number of studies, chronic rhinosinusitis has been
shown to significantly impair QoL [Level Ib] (465, 572, 584, 591, 592) and
this has also been shown to improve significantly with treatment [Level IIb] (459, 486, 585, 587, 593, 594)
Supplement 20
43
7. Management
7-1 Treatment of rhinosinusitis with corticosteroids
The introduction of topically administered glucocorticoids has
improved the treatment of upper (rhinitis, nasal polyps) and
lower (asthma) airway inflammatory disease. The clinical efficacy of glucocorticoids may depend in part on their ability to
reduce airway eosinophil infiltration by preventing their
increased viability and activation. Both topical and systemic
glucocorticoids may affect the eosinophil function by both
directly reducing eosinophil viability and activation (370, 427, 595, 596)
or indirectly reducing the secretion of chemotactic cytokines
by nasal mucosa and polyp epithelial cells (368, 597-599). The potency
of these effects is lower in nasal polyps than in nasal mucosa
suggesting an induced inflammatory resistance to steroid treatment in chronic rhinosinusitis / nasal polyposis (596, 597).
The biological action of glucocorticoids is mediated through
activation of intracellular glucocorticoid receptors (GR) (600),
expressed in many tissues and cells (601) Two human isoforms of
GR have been identified, GR and GR, which originate from
the same gene by alternative splicing of the GR primary transcript (602) . Upon hormone binding, GR ?enhances antiinflammatory or represses proinflammatory gene transcription,
and exerts most of the anti-inflammatory effects of glucocorticoids through protein-protein interactions between GR and
transcription factors, such as AP-1 and NF-B. The GR isoform does not bind steroids but may interfere with the GR*
function. There may be several mechanisms accounting for the
resistance to the antiinflammatory effects of glucocorticoids,
including an overexpression of GR or a downexpression of
GR . Increased expression of GR has been reported in
patients with nasal polyps (603, 604) while downregulation of GR*
levels after treatment with glucocorticoids (605, 606) has also been
postulated to be one of the possible explanations for the secondary glucocorticoid resistance phenomenon.
The anti-inflammatory effect of corticosteroids could, theoretically, be expected as well in non-allergic (i.e. infectious) as in
allergic rhinosinusitis. Tissue eosinophilia is thus also seen in
CRS (259).
Indications for corticosteroids in rhinosinusitis:
Acute rhinosinusitis;
Prophylactic treatment of acute recurrent rhinosinusitis;
Chronic rhinosinusitis without NP;
Chronic rhinosinusitis with NP;
Postoperative treatment of chronic rhinosinusitis with or
without NP.
7-1-1 Acute rhinosinusitis
Most studies on corticosteroids in ARS determine the effect of

topical corticosteroids as adjunct therapy to antibiotics. Very
recently a study is published in which topical corticosteroid
treatment as monotherapy is compared to antibiotics
7-1-1-1 Topical corticosteroid as monotherapy in acute rhinosinusitis
Recently mometasone furoate (MF) has been used and compared to amoxicillin and placebo in ARS (607). MF 200ug twice
daily was significantly superior to placebo and amoxicillin at
improving symptom score. Used once daily MF was also superior to placebo but not to amoxicillin. This randomized study
was done double-blind, double-dummy on 981 subjects. This
is the first study to show topical steroids when used twice daily
are effective in ARS as monotherapy and more effective than
amoxicillin when used twice daily.
7-1-1-2 Topical corticosteroid as adjunct therapy in acute rhinosinusitis
Qvarnberg et al (608) measured the clinical effect of budesonide
(BUD)/placebo as a complement to erythromycin and sinus
washout in a randomized, double-blind study on patients
referred for sinus surgery due to chronic or recurrent acute
maxillary sinusitis. Three months treatment was given to 20
subjects in 2 groups, all without NP. Treatment with BUD
resulted in a significant improvement of nasal symptoms, facial
pain and sensitivity. No significant improvement was seen in
mucosal thickening on x-ray. The final clinical outcome did
not differ between the groups. No side effects of treatment
were noted. It is not possible in this study to distinguish chronic from ARS but all cases were reported to have intermittent
episodes of sinusitis for the last two years.
In a multicentre study Meltzer et al (609) used flunisolide as adjunctive therapy to amoxicillin clavulanate potassium in patients with
ARS or CRS for three weeks and an additional four weeks on
only flunisolide. The overall score for global assessment of efficacy was greater in patients treated with flunisolide than placebo
(p=0.007) after 3 weeks and after 4 additional weeks p=0.08. No
difference was seen on x-ray but inflammatory cells were significantly reduced in flunisolide group compared to placebo.
Barlan et al (610) used BUD as adjunctive therapy to amoxillin
clavulanate potassium for three weeks in a randomized, placebo controlled study in children with ARS. Improvement in
cough and nasal secretion were seen at the end of the second
week of treatment in the BUD group, p<0.05 for both symptoms compared to placebo. At the end of week three there
were no differences between the groups.
Melzer et al (611) gave mometasone furoate (MF) 400 ug to 200
44
Supplement 20
patients and placebo to 207 patients with ARS as adjunctive

therapy to amoxicillin/clavulanate potassium for 21 days. Total
symptom score and individual symptom scores as congestion,
facial pain, headache and rhinorrhea improved significantly,
but not postnasal drip in the MF group. The effect was most
obvious after 16 days treatment. Improvement on CT was seen
in MF group but was not statistically significant. No side
effects of treatment were seen.
In a study by Dolor et al (612) 200 ug FP daily was used as
adjunctive therapy for 3 weeks (to cefuroxime for 10 days and
xylometazoline for 3 days) in a double blind placebo controlled
multicentre trial (n=47 in FP group and 48 in control group) in
patients with ARS. Time was measured to clinical success.
After two weeks, success was seen in 73.9 and 93.5% in placebo
and FP group respectively (p=0.009). Time to clinical success
was 9.5 and 6.0 days respectively (p=0.01)
Nayak et al (613) compared MF 200 and 400 ug to placebo in 325,
318 and 324 patients with ARS (no NP) as adjunctive therapy
to amoxicillin/clavulanate potassium for 21 days treatment.
Total symptom score (TSS) was improved from day 4 and at
the end of the study (21 days) in both MF groups compared to
placebo. Improvement compared to the situation before treatment was 50 and 51% for MF groups and 44% in placebo
group, p<0,017. Individual nasal symptom scores such as nasal
congestion, facial pain, rhinorrhea and postnasal drip improved
in both MF-groups compared to placebo. CT was improved,
but not statistically significant in MF groups compared to

placebo. No side effects of treatment were seen.
All these studies were on study groups where intranasal
steroids have been used as an additional treatment to antibiotics. Only the Meltzer study compares topical corticosteroid
as monotherapy to antibiotics. The findings by Meltzer et al (607)
are of great interest but one might argue that objective references of bacterial infection were lacking (sinus aspirates for
culture) as well as CT or x-ray. There might be a high number
of viral infections but the results are in favour of a more
restricted attitude to antibiotics in ARS. The evidence level as
monotherapy and as adjunctive therapy to systemic antibiotics
is I.
7-1-1-3 Oral corticosteroid as adjunct therapy in acute rhinosinusitis
Gehanno et al (614) tried 8 mg methylprednisolone three times
daily for 5 days as adjunctive therapy to 10 days treatment with
amoxicillin clavulanate potassium in patients with ARS (criteria: symptoms < 10 days, craniofacial pain, purulent nasal discharge with purulent drainage from the middle meatus, opacities of the sinuses in x-ray or CT scan) in a placebo controlled
study. No difference was seen in therapeutic outcome at day 14
between the groups (n=417) but at day 4 there was a significant
reduction of headace and facial pain in the steroid group.
In a multicentre study Klossek et al
(615)
assessed in a double
Table 7-1. Treatment with nasal corticosteroids in acute rhinosinusitis

study
drug
antibiotic
number
effect
X-ray
level of
evidence
Qvarnberg, 1992 (608)
budesonide
erythromycin
20
significant effect on nasal symptoms,

facial pain and sensitivity; final clinical outcome did not differ
mucosal thickening =
no effect
Ib
Meltzer, 1993 (609)
flunisolide
amox/clav
180
significant effect: overall score for

global assessment of efficacy was
greater in the group whith flunisolide
no effect on x-ray
Ib
Barlan, 1997 (610)
budesonide
amox/clav
89 (children)
improvement in cough and nasal secretion seen at the end of the second
week of treatment in the BUD group
not done
Ib
Meltzer, 2000 (611)
mometasone
furoate
amox/clav
407
significant effect in congestion, facial

pain, headache and rhinorrhea. No
significant effect in postnasal drip
no statistical difference
in CT outcome
Ib
Dolor, 2001 (612)
fluticasone
propionate
cefuroxime
axetil
95
significant effect.
effect measured as clinical success
depending on patients self-judgment
of symptomatic improvement
not done
Ib
Nayak, 2002 (613)
mometasone
furoate
amox/clav
967
total symptom score (TSS) was

improved
(nasal congestion, facial pain, rhinorrhea and postnasal drip)
in CT outcome
Ib
Meltzer, 2005
mometasone
furoate
981
significant effect on total symptoms

score, nasal congestion, facial pain,
sinus headache. significantly superior
to placebo and amoxicillin
not done
Ib
(607)
45
Table 7-2. Treatment with oral corticosteroids in acute rhinosinusitis

study
drug
antibiotic
number
effect
effect at end of treatment
level of
evidence
Gehanno, 2000 (614)
8 mg metylprednisolone TDS
amoxicillin
clavulanate
417
significant reduction of headace and

facial pain
at 14 days
Ib
Klossek, 2004 (615)
oral prednisone
cefpodoxime
289
improvement in pain, nasal obstrucno statistical difference

tion and consumption of paracetamol at end of study
during first 3 days
Ib
blind, randomised study in parallel groups the efficacy and tolerance to prednisone administered for 3 days in addition to cefpodoxime in adult patients presenting with an acute bacterial rhinosinusitis (proven by culture) with severe pain. The assessments made during the first 3 days of treatment showed a statistically significant difference in favour of the prednisone group
regarding pain, nasal obstruction and consumption of paracetamol. There was no difference between the two groups after the
end of the antibiotic treatment. The tolerance measured
throughout the study was comparable between the two groups.
Pain is significantly relieved during treatment with prednisone
but after 10 days on antibiotics there was no difference
between the two groups. Evidence level for steroids as pain
reliever: I but there is no evidence for a more positive long
term outcome compared to placebo.
7-1-2 Prophylactic treatment of recurrent episodes of acute rhinosinusitis
In a study by Puhakka et al (616) FP (200 g four times daily) or
placebo were used for 6 days in 199 subjects with an acute
common cold, 24-48 hours after onset of symptoms to study
the preventive effects of FP on risk for development of ARS.
Frequency of sinusitis at day 7 in subjects positive for rhinovirus, based on x-ray, was 18.4% and 34.9% in FP and placebo group respectively (p=0.07) thus indicating a non-significant
effect of FP.
Cook et al. randomized, as a continuation of an acute episode
of rhinosinusitis, patients with at least 2 episodes of rhinosinusitis in the previous 6 months or at least 3 episodes in the
last 12 months for a double blind, placebo-controlled study
with FP, 200 mcg QD. 227 subjects were included. Additionally
cefuroxime axetil 250 mg BID was used for the first 20 days.
39% had a recurrence in the placebo group and 25% in the FP
group (p=0.016) during the seven week follow-up period. Mean
number of days to first recurrence was 97.5 and 116.6 respectively (p=0.011) (617).
There is very low evidence for a prophylactic effect of nasal
corticosteroids to prevent recurrence of ARS episodes.
7-1-3 Chronic rhinosinusitis without nasal polyps
7-1-3-1 Topical corticosteroid chronic rhinosinusitis without
nasal polyps
Parikh et al (618) performed a randomized, double blind, placebo-controlled trial on patients with chronic RS on two groups
with respectively 9 and 13 subjects (2 subjects in each group
with nasal polyps) to test fluticasone propionate for 16 weeks.
No significant improvement was seen, as measured by symptom scores, diary card, acoustic rhinometry or endoscopy. No
side effects were seen in either group.
In another double blind placebo controlled study on patients
with CRS (without NP) with allergy to house dust mite and
who had recently been operated on but still had signs of
chronic RS, 256 ug budesonide (BUD) or placebo was instilled
into the maxillary sinus once a day through a sinus catheter for
three weeks (619). A regression of more than 50% of total nasal
symptom scores was seen in 11/13 in the BUD group and 4/13
in placebo group. The effect was more long term in BUD
group, i.e. 2-12 months compared with less than 2 months in
the placebo group (who had experienced an effect during the
catheter period). A significant decrease was also seen in BUD
group after three weeks treatment for CD-3, eosinophils and
cells expressing IL-4 and IL-5.
In a study by Cuenant et al (620) tixocortol pivalate was given as
endonasal irrigation in combination with neomycin for 11 days
in a double blind placebo controlled in patients with chronic
RS. Maxillary ostial patency and nasal obstruction was signifi-
Table 7-3. Treatment with nasal corticosteroids in prophylaxis of acute rhinosinusitis

study
drug
number
time (weeks)
effect
comments
level of evidence
Puhakka, 1998 (616)
FP
199
N.S.
common cold
Ib
Cook, 2002 (617)
FP
227
increased time to first recurrence.

decreased frequency of ARS
Ib
46
Supplement 20
cantly improved in the tixocortol group compared to placebo.

Patients with CRS without allergy responded better to topical
steroids than those with allergy.
Sykes et al (621) looked on 50 patients with mucopurulent CRS
and allocated them to 3 groups for local treatment with sprays
with either dexamethasone + tramazoline + neomycin/dexamethasone + tramazoline/placebo 4 times daily for 4 weeks and
evaluation was performed double blinded. Treatment in both
active groups was more effective than placebo (discharge,
blockage and facial pain and x-ray) but no difference was seen
with the addition of neomycin to dexamethasone.
A recent multicentre double-blinded placebo-controlled randomised trial of 134 patients with CRS without nasal polyps
treated with topical budesonide for 20 weeks showed significant improvement in a number of parameters including symptom score and nasal inspiratory peak flow (622) Quality of life
assessments did not change however.
There is some evidence for an effect of topical intranasal
steroids in CRS, particularly with intramaxillary instillation of
steroids. No side effects were seen, including no increased
signs of infection with intranasal corticosteroid treatment.
7-1-3-2 Oral corticosteroid chronic rhinosinusitis without nasal
polyps
There are no data showing efficacy of oral corticosteroids in
chronic rhinosinusitis without nasal polyps.
nasal polyps
Mygind et al (623) showed that beclomethasone dipropionate
(BDP) 400ug daily for three weeks reduced nasal symptoms in
19 patients with NP compared to a control group of 16 patients
treated with placebo aerosol. Reduction of polyp size did not
differ in this short treatment study.
In another study with BDP 400 ug daily for four weeks (double
blind, cross over with 9 and 11 subjects in each group),
Deuschl and Drettner (624) found a significant improvement in
nasal symptoms of blockage and nasal patency as measured
with rhinomanometry. Difference in size of polyps was, however, not seen.
Holopainen et al (625) showed in a randomized, double blind,
paralell, placebo controlled study with 400 mcg budesonide
(n=19) for 4 months that total mean score and nasal peak flow
were in favour for budesonide. Polyps also decreased in size in
the budesonide group.
Tos et al (626) also showed that budesonide in spray (128 mcg)
and powder (140 mcg) were both significantly more effective
than placebo (multicentre) concerning reduction of polyp size,
improvement of sense of smell, reduction of symptom score
and overall assessment compared to placebo.
7-1-4 Chronic rhinosinusitis with NP

In studies on the treatment of NP, it is of value to look separately at the effect on rhinitis symptoms associated with polyposis and the effect on the size of nasal polyps per se. Only
placebo controlled studies will be referred to.
Vendelo Johansen (627) tested BUD 400ug daily compared to

placebo for three months in a multicentre, randomized, double
blind study in patients with small and medium-sized
eosinophilic nasal polyps (grade 1-2). Polyps decreased in the
BUD group while an increase was seen in the placebo group.
The difference in polyp score between the groups was significant (p<0.01). Both nasal symptoms (blockage, runny nose,
sneezing) and peak nasal inspiratory flow (PNIF) improved significantly in BUD group.
7-1-4-1
Lildholt et al (491) compared BUD 400 or 800 ug daily with place-
Topical corticosteroid chronic rhinosinusitis with
Table 7-4. Treatment with nasal corticosteroids in chronic rhinosinusitis without nasal polyposis
study
drug
number
time
symptoms
other effects
level of evidence
Cuenant, 1986 (620)
tixocortol
irrigation
60
11 days
nasal obstruction significantly

improved
maxillary ostial patency

significantly improved
Ib
Sykes, 1986 (621)
dexamethasone
+ tramazoline
50
4 wks
discharge, obstruction and facial pain significantly improved
plain x-ray and nasal airway

resistance and mucociliary clearance significant
improved
IIa
Parikh, 2001 (618)
fluticasone
propionate
22
16 wks
not significant
acoustic rhinometry not

significant.
Ib
Lavigne, 2002 (619)
intrasinus
budesonide
26
3 wks
total symptom score significant

improved
T-cells,
eosinophils
mRNA for IL-4, and IL-5
significantly improved
Ib
Lund et al 2004 (622)
budesonide
134
20 wks
significant symptom improvement
significant improvement in
airway using PNIF
Ib
47
bo for four weeks (n=40, 34, 42 respectively). Symptom relief

was significant in both BUD groups compared to placebo but
there was no significant difference in polyp size between the
groups as measured by the investigators. Peak nasal expiratory
flow (PNEF) was significantly improved in the BUD groups and
increased during the study. No difference was noted for sense
of smell. No dose-response correlation was seen.
rhinorrhea and congestion. Twice daily was superior to once

daily regarding congestion/obstruction and both doses significantly increased PNIF
Holmberg et al (628) used FP 400ug, BDP 400 ug and placebo for

26 weeks in a double blind, parallel group, single centre study.
Patients with bilateral polyps, grade 1-2, n=19, 18 and 18
respectively in each group were investigated. There was a significant improvement in symptoms and PNIF for both steroid
groups compared to placebo. No statistically significant differences between the two active groups were seen.
Keith et al (629) compared fluticasone propionate (FP) nasal
drops (FPND) 400 ug daily to placebo in a placebo controlled,
parallel-group, multicentre, randomized study (n=52 in both
groups) for 12 weeks. Polyp reduction was not significant but
nasal blockage and PNIF were significantly improved in FPND
group. A few more cases of epistaxis in the FPND group were
seen. No other side effects were reported.
Penttila et al (630) tried FPND 400 and 800 ug and placebo daily
for 12 days in a randomized, double-blind, multi-centre study
for a dose-response analysis. Nasal symptoms were significantly reduced in both FP groups as well as PNIF. 800 ug FP
improved PNIF more than the lower dose and reduced polyp
size significantly (p<0.01) which was not seen in the 400 ug
group.
Lund et al (538) compared FP 400 ug, BDP 400ug and placebo
(n=10, 10, 9) for 12 weeks in a double-blind, randomized, parallel-group, single-centre study. Polyp score was significantly
improved in FP group. Nasal cavity volume measured with
acoustic rhinometry improved in both active groups. Morning
PNIF improved in both active groups but was quicker with FP.
Overall rhinitis symptoms did not differ statistically between
the groups after 12 weeks treatment.
Hadfield et al (631) looked at treatment of NP in patients with
cystic fibrosis in a randomised, double-blind, placebo controlled study. Betamethasone drops were used in 46 patients
for 6 weeks out of which 22 completed the course. There was a
significant reduction in polyp size in the group treated with
betametasone but no significant difference was seen in the
placebo group.
Mometasone furoate (MF) has been tried in a number of studies as reported by Small et al (632). 354 subjects were divided in
three groups to have either MF 200 ug once or twice daily or
placebo for four months. In both MF groups significant polyp
reduction was seen as well as improvement in loss of smell,
A comparable study was performed by Stjrne et al (633), finding

200 ug twice daily had a significant effect in reducing polyp
size while 200ug once daily was not statistically effective compared to placebo. Both MF doses significantly improved congestion/obstruction as well as PNIF but no improvement in
sense of smell was seen after four months.
A third study also by Stjrne et al (634) compared in 298 subjects
with mild-to-moderate nasal polyposis, treatment with
mometasone furoate nasal spray (MFNS) 200 ug once daily
(QD) in the morning during 16 weeks with placebo. They
found a significantly decrease in nasal congestion, polyp size,
and improved sense of smell, peak nasal inspiratory flow and
quality of life.
Aukema et al. (635) sought to investigate in a 12-week, doubleblind, placebo-controlled study whether treatment with fluticasone propionate nasal drops (FPNDs) can reduce the need for
surgery, as measured by signs and symptoms of nasal polyposis
and chronic rhinosinusitis, in fifty-four patients with severe
nasal polyposis/chronic rhinosinusitis who were on the waiting
list for functional endoscopic sinus surgery (FESS). FESS was
no longer required in 13 of 27 patients treated with FPNDs
versus 6 of 27 in the placebo group (P <. 05). Six patients from
the placebo group dropped out versus 1 from the FPND group.
Symptoms of nasal obstruction, rhinorrhea, postnasal drip, and
loss of smell were reduced in the FPND group (P <. 05). Peak
nasal inspiratory flow scores increased significantly (P <. 01).
Topical corticosteroids sprays have a documented effect on
bilateral NP and also on symptoms associated with NP such as
nasal blockage, secretion and sneezing but the effect on the
sense of smell is not high. There is a high evidence level (Ia)
for effect on polyp size and nasal symptoms associated with
nasal polyposis . For individual symptoms blockage responds
best to corticosteroids but improvement in sense of smell is
not so obvious. Nasal drops are more effective than nasal spray
and have a significant positive effect on smell (Ib).
7-1-4-2 Side effects of topical corticosteroid for chronic rhinosinusitis with nasal polyps
Intranasal administration of corticosteroids is associated with
minor nose bleeding in a small proportion of recipients. This
effect has been attributed to the vasoconstrictor activity of the
corticosteroid molecules, and is considered to account for the
very rare occurrence of nasal septal perforation (636). However, it
should be remembered that minor nose bleeds are common in
the population, occurring in 16.5% of 2197 women aged 50-64
years over a one year study (637). Nasal biopsy studies do not
show any detrimental structural effects within the nasal mucosa
48
Supplement 20
Table 7-5. Treatment with nasal corticosteroids in chronic rhinosinusitis with nasal polyposis
study
drug
number
treatment time
(weeks)
effect on nasal symptoms

(*stat sig)
objective measures
(*stat sig)
effect on polyps
Mygind, 1975 (623)
BDP
35
total symptom score*
Deuschl, 1977 (624)
BDP
20
2x4weeks
Holopainen, 1982 (625)
Bud
19
Vendelo Johansen,
1993 (627)
Bud
Lildholt, 1995 (491)
n.s.
Ib
blockage*
rhinomanometry*
n.s.
Ib
16
nasal peak flow*

eosinophilia*
yes
Ib
91
12
blockage*
sneezing*
secretion*
sense of smell N.S.
nasal peak inspiratory

flow *
yes
Ib
Bud
116
blockage*
sneezing*
secretion*
sense of smell N.S.
nasal peak expiratory

flow*
yes
Ib
Holmberg, 1997 (628)
FP/BDP
55
26
over all assessment*

flow*
yes in BDP
Ib
Tos , 1998 (626)
Bud
138

sense of smell*
yes
Ib
Lund, 1998 (538)
FP/BDP
29
12
blockage*
rhinitis N.S.

flow*
acoustic rhinometry*
yes FP
Ib
Keith, 2000 (629)
FPND
104
12
blockage*
rhinitis*
sense of smell N.S.

flow*
olfactory test N.S.
n.s.
Ib
Penttil, 2000 (630)
FP
142
12
blockage*
rhinitis*
sense of smell N.S.

flow*
olfactory test*
yes
Ib
Hadfield, 2000 (631)
betametasone
46 CF
children
N.S.
yes
Ib
Aukema 2005 (635)
fluticasone
propionate
nasal drops
54
12
nasal obstruction *
rhinorrhea * postnasal
drip *
and loss of smell *

flow*
CT scan
yes
Ib
Small et al 2005 (632)
Mometasone
354
16
obstruction*
loss of smell*
rhinorrhea*

flow*
yes
Ib
Stjrne et al 2006 (633)
Mometasone
310
16
obstruction*
loss of smell N.S.
rhinorrhea*

flow*
200ug OD no
200ug BID yes
Ib
Stjrne et al 2006
Mometasone
298
16
obstruction*
loss of smell *
rhinorrhea*
QOL

flow*
yes
Ib
(634)
with long-term administration of intranasal corticosteroids (638).

Much attention has focused on the systemic safety of intranasal
application. The systemic bioavailability of intranasal corticosteroids varies from <1% to up to 40-50% and influences the risk
of systemic adverse effects (636). Potential adverse events related
to the administration of intranasal corticosteroids are effects on
growth, ocular effects, effects on bone, and on the hypothalamic-pituitary-adrenal axis (639). Because the dose delivered topically
is small, this is not a major consideration, and extensive studies
have not identified significant effects on the hypothalamic-pituitary-adrenal axis with continued treatment. A small effect on
growth has been reported in one study in children receiving a
standard dosage over 1 year. However, this has not been found
level of
evidence
in prospective studies with the intranasal corticosteroids that

have low systemic bioavailability and therefore the judicious
choice of intranasal formulation, particularly if there is concurrent corticosteroid inhalation for asthma, is prudent (640). In summary, intranasal corticosteroids are highly effective; nevertheless, they are not completely devoid of systemic effects. Thus,
care has to be taken, especially in children, when long-term
treatments are prescribed.
7-1-4-3 Systemic corticosteroids in chronic rhinosinusitis with
nasal polyps
Traditionally systemic steroids have been used in patients with
NP although no placebo-controlled studies or dose-effect stud-
49
ies have supported the concept. The clinical acceptance that

systemic steroids have a significant effect on NP are supported
by open studies where a single injection of 14 mg betametasone have been compared with snare polypectomy surgery (493,
641)
. In these studies effects are seen on nasal polyp size, nasal
symptom score and nasal expiratory peak flow but it is difficult
to differentiate the effect of systemic steroids from that of topical treatment since both treatments were used at the same
time. The control groups underwent surgery during the study
period.
Hissaria et al compared 50 mg prednisolone daily for 14 days

with placebo (576). A significant improvement was found in nasal
symptoms (obstruction, secretion, sneezing, sense of smell),
endoscopic findings of polyp size and MRI scores supporting
the effect of systemic steroids on NP.
There is no study available on depot injection of corticosteroids or local injection into polyps or the inferior turbinate.
These types of treatment are actually obsolete, because of the
risk of fat necrosis at the site of the injection or blindness following endonasal injection.
In another open study oral prednisolone was given in doses of

60 mg to 25 patients with severe polyposis for four days and for
each of the following 12 days the dose was reduced by 5 mg
daily. Antibiotics and antacids were also given. 72% experienced a clear improvement due to involution of polyps (642) and
in 52% a clear improvement was seen on CT. In particular
nasal obstruction and the sense of smell were reported to
improve. Out of 22 subjects treated, 10 were polyp free based
on anterior rhinoscopy 2 weeks 2 months after therapy.
Studies on systemic steroids in NP has recently been published

giving support to the clinical impression that they are effective
after two weeks use in doses acceptable for a majority of
patients. As well as symptom relief, an effect on polyp size and
MRI changes are seen. Evidence level:Ib.
7-1-4-4 Side effects of systemic corticosteroids in chronic rhinosinusitis with nasal polyps
The anti-inflammatory effects of corticosteroids cannot be separated from their metabolic effects as all cells use the same
glucocorticoid receptor; therefore when corticosteroids are prescribed measures should be taken to minimize their side
effects. Clearly, the chance of significant side effects increases
with the dose and duration of treatment and so the minimum
dose necessary to control the disease should be given.
Damm et al. (643) showed a good effect with combined treatment using topical steroids (budesonide, unknown doses) and
oral treatment with fluocortolone 560 mg or 715 mg in 2 different groups of patients with 20 severe cases of CRS with NP.
This study was not controlled. A large improvement of symptoms was seen (80%) and improvement on MRI (>30% reduction of MRT-pathology) was observed in 50%.
As a guide for oral treatment, the approximate equivalent

doses of the main corticosteroids in terms of their glucocorticoid (or anti-inflammatory) properties are listed below (645).
Recently, however, two well designed studies have shown

effect of systemic steroids in NP. Benitez et al (644) performed a
randomized placebo controlled study with prednisone for two
weeks (30 mg 4 days followed by a 2-day reduction of 5 mg).
After two weeks on prednisone or placebo, the prednisone
group continued for ten weeks on intranasal BUD. After two
weeks treatment a significant polyp reduction was seen, several
symptoms improved and anterior rhinomanometry improved
compared to the placebo group. After 12 weeks a significant
reduction of CT-changes were seen in the steroid treated
group.
7-1-5 Postoperative treatment with topical corticosteriods for

chronic rhinosinusitis with NP to prevent recurrence of polyps
There are a couple of studies on nasal steroids used after surgical resection of polyps.
Drettner et al (646) used flunisolide 200 g daily for 3 months in a
double-blind, placebo controlled study with 11 subjects in both
groups. A statistically significant effect was seen on nasal
symptoms but not on polyp score.
In a double-blind randomized, placebo controlled study,
Virolainen and Puhakka
(647)
tested 400 g BDP in 22 patients
Table 7-6. Treatment with systemic corticosteroids in chronic rhinosinusitis with NP

study
drug
number
dose/time
betametamethasone/BDP
53
?/52 weeks
Lildholt, 1997
effect symptoms
yes
effect polyps
level of evidence
yes
III
yes
III
betametamethasone/budesonide
16
14mg/52 weeks
yes
van Camp, 1994 (642)
prednisolone 60 mg
25
2 weeks
72%
betametamethasone/budesonide
16
14mg/52 weeks
yes
Damm, 1999 (643)
budesonide + fluocortolone
20
yes
III
Benitez , 2006 (644)
prednisone + Budesonide
84
2 weeks/10 weeks
yes
yes
Ib
Hissaria, 2006 (576)
prednisolone
41
50mg/2 weeks
yes
yes
Ib
(493)
yes (10/22)
yes
III
III
50
Supplement 20
randomized study in 162 patients with CRS with or without

nasal polyps after FESS following failure of nasal steroid treatment. Patients were randomized and given FPANS 400 microg
b.i.d., FPANS 800 g b.i.d. or placebo b.i.d. for the duration of 1
year after FESS combined with peri-operative systemic corticosteroids. No differences in the number of patients withdrawn
because of recurrent or persistent diseases were found between
the patients treated with FPANS and patients treated with
placebo. Also no positive effect was found for FPANS compared with placebo in several subgroups such as patients with
nasal polyps, high score at FESS or no previous sinus surgery.
Table 7-7. Equivalence table of oral corticosteroids

Betamethasone
0.75 mg
Cortisone acetate
25 mg
Dexamethasone
0.75 mg
Hydrocortisone
20 mg
Methylprednisolone
4 mg
Prednisolone
5 mg
Prednisone
5 mg
Triamcinolone
4 mg
and placebo in 18 in a randomized, double blind study. After

one year of treatment 54% in BDP group were polyp free compared to 13% in the placebo group. No statistics were given.
86% in BDP group were free of nasal symptoms compared to
60% in placebo group.
Karlsson and Rundkrantz (648) treated 20 patients with BDP and
20 were followed with no treatment for NP (no placebo treatment) for 2.5 years. BDP was given 400 g daily for the first
month and then 200 g daily. There was a statistically significant difference between the groups after 6 months in favour of
BDP, which increased during the study period of 30 months.
Dingsor et al. (649) used flunisolide 2x25 g on both sides twice
daily (200 g) after surgery in a placebo controlled study for 12
months (n=41). Flunisolide was significantly better than placebo at both 6 and 12 months both with respect to number and
size of polyp recurrence.
Hartwig et al. (650) used budesonide 6 months after polypectomy
in a double blind parallell-group on 73 patients. In the budesonide group, polyp scores were significantly lower than controls after 3 and 6 months. This difference was only significant
for patients with recurrent polyposis and not for those operated on for the first time.
Dijkstra et al (651) performed a double-blind placebo-controlled
Rowe Jones et al (652) studied a similar group of one hundred

nine patients studied prospectively for 5 years postoperatively.
Seventy two patients attended the 5 year follow-up visit. The
patients were entered into a randomised, stratified, prospective, double-blind placebo controlled study of fluticasone propionate aqueous nasal spray 200 g twice daily, commencing 6
weeks after FESS. The change in overall visual analogue score
was significantly better in the FPANS group at 5 years. The
changes in endoscopic oedema and polyp scores and in total
nasal volumes were significantly better in the FPANS group at
4 years but not 5 years. Last value carried forward analysis
demonstrated that changes in endoscopic polyp score and in
total nasal volume was significantly better in the FPANS group
at 5 years. Significantly more prednisolone rescue medication
courses were prescribed in the placebo group.
Postoperative effect on recurrence rate of NP after polypectomy with intranasal steroids is well documented and the evidence level is Ib. Two studies describe the effect after FESS in
a group of patients who underwent FESS after inadequate
response to at least three months topical corticosteroid treatment. The studies show conflicting results though the reasons
are not clear.
7-1-6 Side-effects of corticosteroids
Table 7-8. Nasal corticosteroids in the post operative treatment of persistant rhinosinusitis to prevent recurrences of NP
study
drug
number
treatment
time (weeks)
effect on nasal symptoms

(*stat sig)
Virolainen, 1980 (647)
BDP
40
52
blockage
anterior rhinoscopy yes
IV
Drettner , 1982 (646)
flunisolide
22
12
total nasal score

(blockage,secretion sneezing)*
anterior rhinoscopy N.S.
Ib
Karlsson, 1982 (648)
BDP
40
120
not described
IIa
Dingsor, 1985 (649)
flunisolide
41
52
blockage*
sneezing*
Ib
Hartwig, 1988 (650)
BUD
73
26
blockage N.S.
Ib
Dijkstra 2004
fluticasone
propionate
162
52
not seen
nasal endoscopy not seen.
Ib
fluticasone
propionate
109
5 years
overall visual analogue score
endoscopic polyp score and

in total nasal volume
Ib
(651)
Rowe-Jones 2005 (652)
effect on polyp recurrence

(method of test)
level of evidence
51
The safety of nasal and oral corticosteroids has been the subject
of concern in medical literature since many patients with chronic
sinus disease are prescribed these drugs due to their good efficacy. Suppression of the hypothalamic-pituary-adrenal axis, osteoporosis or changes in bone mineral density, growth retardation in
children, cataracts and glaucoma have been reported to be the
main adverse effects of corticosteroid treatment (653). In relation to
adverse effects of corticosteroids, it is obvious that a clear distinction needs to be made between nasal and oral corticosteroids.
Nasal corticosteroid treatment represents one of the long-term
treatment modalities in patients with chronic sinus disease. It
is well established that absorption into the systemic circulation
takes place after nasal administration of corticosteroids.
However, several factors influence the systemic absorption,
like the molecular characteristics of the corticosteroid, the prescribed dose, the mode of delivery and the severity of the
underlying disease (653). There is insufficient evidence from the
literature to relate the use of nasal corticosteroids at licensed
doses to changes in bone mineral biology, cataract and glaucoma. Adrenal suppression may occur with some nasal corticosteroids at licensed doses, but the clinical relevance remains
uncertain. Overuse of nasal corticosteroids may be responsible
for adrenal insufficiency and decrease in bone mineral density
(654)
. Of note, inhaled corticosteroids are the mainstay of treatment for children and adults with asthma and are more often
associated with systemic side effects than the nasal route of
treatment for rhinosinusitis (655).
Nasal corticosteroid-induced septal perforation is rarely
described in literature (656). Whether septal perforation relates to
repeated traumas of the nasal mucosa and septal cartilage by
the nasal device, to the underlying nasal disorder for which
corticosteroids were prescribed or to a direct adverse effect of
the steroid used, remains unclear.
Short treatment with oral corticosteroids is effective in chronic
rhinosinusitis with nasal polyps. It is obvious that repeated or
prolonged use of oral corticosteroids is associated with a significantly enhanced risk of the above mentioned side effects (657).
newer, non-penicillin antibiotic versus penicillin class (n=10);

and amoxicillin-clavulanate versus other extended spectrum
antibiotics (n=17), where n is the number of trials. Most trials
were conducted in otolaryngology settings. Only 8 trials
described adequate allocation and concealment procedures; 20
were double-blinded.
Compared to control, penicillin improved clinical cures [relative risk (RR) 1.72; 95% confidence interval (CI) 1.00 to 2.96].
For the outcome of cure or improvement, 77.2% of penicillintreated participants and 61.5% of control participants were
responders. Individuals treated with penicillin were more likely
to be cured [RR 1.72; 95% CI 1.00 to 2.96] or cured/improved
[RR 1.24; 95% CI 1.00 to 1.53]. Rates for cure or improvement
were 82.3% for amoxicillin and 68.6% for placebo. Participants
treated with amoxicillin were not more likely to be cured than
with placebo [RR 2.06; 95% CI 0.65 to 6.53] or cured/improved
[RR 1.26; 95% CI 0.91 to 7.94] but there was significant variability between studies. Radiographic outcomes were improved by
antibiotic treatment. (40).
Comparisons between newer non-penicillins (cephalosporins,
macrolides, minocycline), versus penicillins (amoxicillin, penicillin V) showed no significant differences [RR for cure 1.07;
95% CI 0.99 to 1.17]; Rates for cure or improvement were 84%
for both antibiotic classes. Drop-outs due to adverse events
were infrequent, and. these rates were not significantly different [RR 0.61; 95% CI 0.33 to 1.11]. Cumulative meta-analysis of
studies ordered by year of publication (a proxy for prevalence
of beta-lactamase-producing organisms) did not show a trend
towards reduced efficacy of amoxicillin compared to newer
non-penicillin antibiotics.
Because macrolides are bacteriostatic and cephalosporins bactericidal, subgroup analyses were performed to determine if
one of these two classes were superior to penicillins. In the
subgroup analyses, cephalosporins and macrolides showed
similar response rates compared to penicillins.
7-2 Treatment of rhinosinusitis with antibiotics

7-2-1 Acute community acquired rhinosinusitis
Although more than 2000 studies on the antibiotic treatment
of ARS have already been published, only 49, involving 13,660
participants, meet the Cochrane Board criteria for placebo control, statistical analysis, sufficient sample sizes, and the description of clinical improvements or success rates (40).
Primary outcomes were:
a. clinical cure;
b. clinical cure or improvement.
Secondary outcomes were:
a. radiographic improvement;
b. relapse rates;
c. dropouts due to adverse effects.
Major comparisons were antibiotic versus control (n=3) (658-660);
Sixteen trials, involving 4818 participants, compared a newer

non-penicillin antibiotic (macrolide or cephalosporin) to amoxicillin-clavulantate. Three studies were double-blind. Rates for
cure or improvement were 72.7 % and 72.9 % for newer nonpenicillins and amoxicillin-clavulanate respectively. Neither
cure rates (RR 1.03; 95% CI 0.96 to 1.11) nor cured/improvement rates (RR 0.98; 95% CI 0.95 to 1.01), differed between the
groups. Compared to amoxicillin-clavulanate, dropouts due to
adverse effects were significantly lower for cephalosporin
antibiotics (RR 0.47; 95% CI 0.30 to 0.73). Relapse rates within
one month of successful therapy were 7.7% and did not differ
between the groups.
Six trials, of which 3 were double blind, involving 1,067 partici-
52
The reviewers conclude that in acute maxillary sinusitis confirmed radiographically or by aspiration, current evidence is
limited but supports the use of penicillin or amoxicillin for 7 to
14 days. Clinicians should weigh the moderate benefits of
antibiotic treatment against the potential for adverse effects (40).
It is interesting to see that in this review the local differences
in susceptibility of micro-organisms to the antibiotics used is
not acknowledged, although total cumulative meta-analysis of
studies ordered by year of publication did not show a trend
towards reduced efficacy of amoxicillin compared to newer
non-penicillin antibiotics. Resistance patterns of predominant
pathogens like Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, vary considerably (47, 48). The
prevalence and degree of antibacterial resistance in common
respiratory pathogens are increasing worldwide. The association between antibiotic consumption and the prevalence of
resistance is widely assumed (50). Thus the choice of agent may
not be the same in all regions, as selection will depend on local
resistance patterns and disease aetiology. (50, 661). Moreover one
might wonder whether the limited benefits of antibiotic treatment outweigh the considerable threat of antibiotic resistance.
In 1995, upper respiratory tract infection was the most frequent
reason for seeking ambulatory care in the United States, resulting in more than 37 million visits to physician practices and
emergency departments (662).
Short-term Therapeutic Intervention for Acute Disease

Applicable for studies of short-term treatment for acute
rhinosinusitis, including studies of:
anti-infectives
anti-inflammatory drugs
Symptom relievers
active treatment
placebo
difference in time to
improvement
Time Units
end of study
(i.e. 3-12
weeks)
end of
therapy
(variable
duration)
Relevant for the discussion about the efficacy of antibiotics in

ARS is the recently published paper from the (mainly US)
Rhinosinusitis Initiative: Rhinosinusitis: Developing guidance
for clinical trials (6, 673). This group of experts gave advice to
7-2-2-1 Introduction
It is significantly more difficult to evaluate the efficacy of
antibiotic treatment in CRS compared to ARS, because of the
conflicts in terms of terminology and definition of the clinical
picture of CRS in the literature. In most studies, no radiological diagnosis, such as CT, has been performed confirm the
diagnosis of chronic rhinosinusitis. The data supporting the
use of antibiotics in this condition, however, are limited and
lacking in terms of randomized placebo controlled clinical
trials.
randomize
treatement or
placebo
Two studies comparing real life ARS treatment, with the

diagnosis based on symptoms but not bacteriologically proven
(607, 672)
both showed no benefit treating patients with acute rhinosinusitis with antibiotics. Although more and more data
point to a very limited effect of antibiotics in ARS, there are a
limited group of patients, e.g. patients with immunodeficiencies that do benefit from antibiotics. We are in need of simple
tests in the general practice that can discriminate the small
group who would potentially benefit from antibiotics from the
large group that has no benefit from the treatment but puts a
burden on the resistance problems.
7-2-2 Antibiotics in chronic rhinosinusitis
symptoms at
least
7-10 days
Since the publication of the Cochrane review (40) a number of

new studies have been published. Most are non-inferiority
studies comparing two or three antibiotics (663-668). These noninferiority studies also show that a short short course of antibiotics is as good as a long course of antibiotics (665, 669-671).
determine the effect of a treatment intervention on the clinical

course of ARS, as measured by time to resolution of symptoms. Because most antimicrobial trials have demonstrated
clinical cure rates of 80% to 90% at 14 days, the Rhinosinusitis
Initiative committee believed that it was important to demonstrate superiority to existing therapies by showing significant
differences in time to symptom resolution or time to significant improvement based on total symptom score.
Symptoms Score, or impact on Quality of Life
pants, compared a tetracycline (doxycycline, tetracycline,

minocycline) to a heterogeneous mix of antibiotics (folate
inhibitor, cephalosporin, macrolide, amoxicillin). No relevant
differences were found.
Supplement 20
Primary Efficay Endpoint

Time to sympton resolution
Secondary efficary endpoint
QOL
Figure 7-1. Adapted from Rhinosinusitis: Developing guidance for clinical trials (6, 673). The rationale for the illustrated study design is to determine the effect of a treatment intervention on the clinical course of
ARS, as measured by time to resolution of symptoms. Patient symptoms, QOL, or both are measured on the y-axis, and time is measured
on the x-axis. The therapeutic intervention that is to be tested can be
compared with either placebo or a comparator intervention. Success of
the treatment intervention is based on a statistically significant difference in rate of symptom (or QOL) resolution between the comparator
interventions. This graph is intended to convey the conceptual aspects
of the type of study design. Therefore variables, such as timing of intervention, duration of treatment, type of intervention, and end of study,
can be modified based on the specifics of the proposed study. Modified
from Meltzer et al Rhinosinusitis:developing guidance for clinical trials
53
7-2-2-2 Short-term treatment with antibiotics in chronic rhinosinusitis

In a retrospective study, McNally et al (674) reported patient
symptoms and physical examination findings in a cohort of 200
patients with CRS who were treated with a combination of 4
weeks of oral antibiotics, as well as topical corticosteroids and
other adjunctive medications. All patients subjectively
improved in response to therapy after 1 month.
riological eradication rates were 59% and 89% for ciprofloxacin

versus 51% and 91% for amoxicillin/clavulanic acid respectively. These differences were not significant. However, amongst
patients who had a positive initial culture and who were evaluated 40 days after treatment, ciprofloxacin recipients had a significantly higher cure rate than those treated with
amoxicillin/clavulanic acid (83.3% vs. 67.6%, p = 0.043).
Clinical tolerance was significantly better with ciprofloxacin (p
= 0.012), largely due to a large number of gastro-intestinal
related side-effects in the amoxicillin/clavulanic acid group (n
= 35). Ciprofloxacin proved to be at least as effective as amoxicillin/clavulanic acid.
Subramanian et al (675) retrospectively studied a group of 40

patients with CRS who were treated with a combination of 4 to
6 weeks of antibiotics and a 10-day course of systemic corticosteroids. Outcome measures, including comparison of pre- and
post-treatment CT scan, as well as patient symptom scores,
revealed improvement in both outcome parameters in 36 of 40
patients. In the latter study, 24 of 40 patients had sustained
improvement for at least 8 weeks, which would seem to imply
that whatever infection was present was fully eradicated in
these patients.
In a prospective study by Legent et al. (676), 251 adult patients
with CRS were treated in a double-blind manner with
ciprofloxacin vs. amoxicillin/clavulanic acid for 9 days. Only
141 of the 251 patients had positive bacterial cultures from the
middle meatus at the beginning of the study. At the end of the
treatment period, nasal discharge disappeared in 60% of the
patients in the ciprofloxacin group and 56% of those in the
amoxicillin/clavulanic acid group. The clinical cure and bacte-
The efficacy and safety of amoxicillin/clavulanic acid

(AMX/CA) (875/125 mg b.i.d. for 14 days) were compared
with that of cefuroxime axetil (500 mg b.i.d. for 14 days) in a
multicentre, open, parallel-group, randomized clinical trial in
206 adults with chronic or acute exacerbation of CRS by a polish group. Clinical response was similar, with 95% of
AMX/CA-, and 88% of cefuroxime-treated, clinically evaluable
patients cured. In bacteriologically evaluable patients, cure
rates, defined as eradication of the original pathogen with or
without re-colonization with non-pathogenic flora, were also
similar, with 65% of AMX/CA- and 68% of cefuroxime-treated
patients cured. However, clinical relapse was significantly higher in the cefuroxime group: 8% (7/89) of clinically evaluable
patients, compared with 0% (0/98) in the AMX/CA (p=0.0049)
group (677).
Table 7-9. Short Term Antibiotics in Chronic Rhinosinusitis

study
drug
number
time/dose
effect on symptoms
evidence
(678)
ceflaclor
vs. amoxycillin
56 ARS
25 recurrent
rhinosinusitis
15 chronic maxillary sinusitis
2x 500mg
3x500mg
for 10 days
clinical improvement:
ARS 86%
recurrend 56%
CRS.
no statistics
Ib
Legent et al, 1994 (676)
ciprofloxacin
vs. amoxycillin
clavulanate
251
9 days
nasal discharge disappeared:

cipro 60%
amx/clav: 56%
clinical cure:
cipro 59%
amx/clav 51%
bacterological eradication:
cipro 91%
amx/ clav 89%
Ib
McNally et al,
1997 (674)
oral antibiotics
200
4 weeks
yes, subjectively after 4 weeks
III
Subramanian et al;
2002 (675)
antibiotics
10 days corticosteroids
40
4 6 weeks
yes, pre-/ posttreatment CT in 24 patients also improvement after 8 weeks
III
Namyslowski et al,
2002 (677)
amoxycillin clavulanate
vs. cefuroxime axetil
206
875/125mg for
14 days
500mg
for 14 days
clinical cured:
amx/ca 95%
cefurox 88%
bacterial eradication:
amx/ca 65%
cefurox 68%
clinical relapse:
amx/ca 0/ 98
cefurox 7/89
Ib
Huck et al, 1993
54
Supplement 20
Huck et al. compared in a double-blind, randomized trial compared cefaclor with amoxicillin in the treatment of 56 acute, 25
recurrent, and 15 chronic maxillary sinusitis: Whether treated
with cefaclor or amoxicillin, clinical improvement occurred in
86% of patients with ARS and 56% of patients with recurrent
RS. Patients with CRS were too few to allow statistical analysis. The susceptibility of organisms isolated to the study drugs
was unrelated to outcome (678).
To summarize, at the moment no placebo-controlled studies
on the effect of antibiotic treatment are available. Studies comparing antibiotics have level II evidence and do not show significant differences between ciprofloxacin vs. amoxycillin/clavulanic acid, and cefuroxime axetil. The few available prospective
studies show effect on symptoms in 56% to 95% of the patients.
It is unclear which part of this effect is regression to the mean
because placebo controlled studies are lacking. There is urgent
need for randomized placebo controlled trials to study the
effect of antibiotics in CRS and exacerbations of chronic rhinosinusitis.
7-2-2-3 Long-term treatment with antibiotics in chronic rhinosinusitis
The efficacy of long term treatment with antibiotics in diffuse
panbronchiolitis, a disease of unclear aetiology, characterized
by chronic progressive inflammation in the respiratory bronchioles inspired the Asians in the last decade to treat CRS in
the same way (679, 680). Subsequently a number of clinical reports
have stated that long-term, low-dose macrolide antibiotics are
effective in treating CRS incurable by surgery or glucocorticosteroid treatment, with an improvement in symptoms varying
between 60% and 80% in different studies (23, 679, 681, 682). The
macrolide therapy was shown to have a slow onset with ongoing improvement until 4 months after the start of the therapy.
In animal studies macrolides have increased mucociliary transport, reduced goblet cell secretion and accelerated apoptosis of
neutrophils, all factors that may reduce the symptoms of
chronic inflammation. There is also increasing evidence in
vitro of the anti-inflammatory effects of macrolides. Several
studies have shown macrolides inhibit interleukin gene expression for IL-6 and IL-8, inhibit the expression of intercellular
adhesion molecule essential for the recruitment of inflammatory cells. However, it remains to be established if this is a clinically relevant mechanism (683-689).
There is also evidence in vitro, as well as clinical experience,
showing that macrolides reduce the virulence and tissue damage caused by chronic bacterial colonization without eradicating the bacteria. In addition long term treatment with antibiotics has been shown to increase ciliary beat frequency (690). In a
prospective RCT from the same group (536) ninety patients with
polypoid and nonpolypoid CRS were randomised to medical
treatment with 3 months of an oral macrolide (erythromycin)
or endoscopic sinus surgery and followed over one year.
Outcome assessments included symptoms (VAS), the
SinoNasal Outcome Test (SNOT-22), Short Form 36 Health
Survey (SF36), nitric oxide, acoustic rhinometry, saccharine
clearance time and nasal endoscopy. Both the medical and sur-
Table 7-10. Long-term treatment with antibiotics in chronic rhinosinusitis

study
drug
number
time/dose
effect symptoms
level of
evidence
Gahdhi et al,
1993 (682)
prophylatic
antibiosis
details not
mentioned
26
not mentioned
19/26 decrease of acute exacerbation by 50%

7/26 decrease of acute exacerbation by less than 50%
III
Nishi et al,
1995 (681)
clarithromycin
32
400mg /d
pre- and post-therapy assesment of nasal clearence
III
Scadding et al
1995 (690)
oral antibiotic
therapy
10
3 month
increased ciliary beating
III
Ichimura et al,
1996 (23)
roxithromycin
20
clinical improve-ment and polyp-shrinkage in 52%
III
roxithromycin
and azelastine
20
150mg /d
for at least 8 weeks
1mg /d
Hashiba et al,
1996 (679)
clarithromycin
45
400mg /d
for 8 to 12 weeks
clinical improvement in 71%
III
Suzuki et al,
1997 (680)
roxithromycin
12
150mg /d
CT scan pre- and post-therapy: improvment in the aeration

of nasal sinuses
III
Ragab et al
2004 (536)
erythromycin
v ESS
45 in each
arm
3 months
improvement in upper & lower RT symptoms, SF36, SNOT22, NO, Ac Rhin, SCT, nasal endoscopy at 6 & 12 mnths
Ib
Wallwork 2006
roxithromycin
64
3 months
improvements in global rating of patients
Ib
clinical improve-ment and polyp shrinkage in 68%
(691)
RT: respiratory tract; SF 36: Short Form 36 QoL; SNOT-22: SinoNasal Outcome Test; NO:expired nitric oxide, Ac Rhin: acoustic rhinometry; SCT:
saccharine clearance time.
55
gical treatment of CRS significantly improved almost all subjective and objective parameters, with no significant difference
between the two groups nor between polypoid and nonpolypoid CRS except for total nasal volume which was greater after
surgery and in the polypoid patients.
tered thrice daily to the nasal passages by means of a large-particle nebulizer apparatus for 4 weeks in twenty patients with
CRS refractory to medical and surgical therapy. He found no
significant difference between the groups and concluded that
large-particle nebulized aerosol therapy may offer a safe and
effective management alternative for patients with refractory
rhinosinusitis irrespective of the addition of gentamicin (698).
Wallwork et al (691) conducted a double-blind, randomized,

placebo-controlled clinical trial on 64 patients with CRS.
Subjects received either 150 mg roxithromycin daily for 3
months or placebo. The description of the patient populations
is limited, but patients with NP were excluded (personal communication by author). They showed a significant improvement in global patient rating compared to placebo. The other
comparisons were made between pre- and post-treatment situations. In this comparison a statistically significant improvement was found in SNOT-20 score, nasal endoscopy, saccharine transit time, and IL-8 levels in lavage fluid (P<.05) in the
macrolide group. A correlation was noted between improved
outcome measures and low IgE levels.
The benefit of long-term, low-dose macrolide treatment seems
to be that it is, in selected cases, effective when topical steroids
and short courses of antibiotics fail. The exact mechanism of
action is not known, but it probably involves downregulation
of the local host immune response as well as a downgrading of
the virulence of the colonizing bacteria. Placebo-controlled
studies should be performed to establish the efficacy of
macrolides if this treatment is to be accepted as evidencebased medicine.
7-2-3 Exacerbations of chronic rhinosinusitis
7-2-3-1 Short-term treatment with oral antibiotics in acute
exacerbations of chronic rhinosinusitis chronic rhinosinusitis
In open trials, oral antibiotics have an effect on the symptomatology of acute exacerbations of CRS (677, 692). In some of these
studies patients with ARS or CRS are combined with patients
with acute exacerbations of CRS (693, 694). No studies have shown
efficacy of antibiotics in acute exacerbations of CRS in a double blind placebo controlled manner.
In conclusion data on the treatment of acute exacerbation of
CRS are mostly level IV evidence and include oral and local
antibiotics. Double-blind data show a positive effect of the
addition of topical corticosteroid treatment to oral antibiotics
in the treatment of acute exacerbation of CRS.
7-2-3-2 Short-term treatment with local antibiotics in acute
exacerbations of chronic rhinosinusitis
Some studies have compared the effects of local antibiotics in
CRS and acute exacerbation of CRS (620, 695-697).
Desrosiers studied in a randomized, double-blind trial of
tobramycin-saline solution versus saline-only solution adminis-
Sykes found no additional effect with the addition of neomycin

to a spray containing dexamethasone and tramazoline four
times daily to both nostrils for 2 weeks (621).
However, Mosges and Leonard did find differences between
local antibiotics and placebo (695, 697). Mosges showed a positive
effect for fusafungine nasal spray as early as the first 24h of
treatment which was not seen in the placebo group. The
antimicrobiological effect of this preparation is unclear.
Schienberg et al. studied the effectiveness of aerosol delivery
of antibiotics to the sinuses via a nebulizer in 41 patients who
had chronic, recurrent rhinosinusitis that had persisted despite
endoscopic sinus surgery (ESS) and that had not responded to
multiple courses of oral antibiotics. Following 3 to 6 weeks of
treatment, 34 patients (82.9%) experienced either an excellent
or good response to treatment. Side effects were infrequent,
mild, and transient. They concluded that nebulized antibiotics
should be considered for all patients with CRS who have
undergone ESS and who have failed to respond to oral antibiotics or who do not tolerate them (699).
Further studies with better characterized patient populations
are needed.
7-2-4 Side-effects of antibiotics
Common side effects of antibiotics include sickness, diarrhoea,
and, in women, vaginal yeast infections. Some side effects are
more severe and, depending on the antibiotic, may influence
kidney and liver function. Rarely the bone-marrow or other
organs are affected. Blood tests are used to monitor such
adverse reactions.
Some people who receive antibiotics develop colitis, an inflammation of the large intestine. The colitis results from a toxin
produced by the bacterium, Clostridium difficile, which grows
unchecked when other antibacteria are killed by the antibiotics.
Antibiotics can cause allergic reactions. Most are mild allergic
reactions and consist of an itchy rash or slight wheezing.
Patients claiming allergic reactions to antibiotics actually mean
side-effects. This is important to realize because on one hand
severe allergic reactions (anaphylaxis) can be life threatening,
on the other hand some patients claim to be allergic to many
different classes of antibiotics making treatment difficult. Most
adverse events related to antimicrobials are reversible rapidly
on cessation of the medication. Irreversible toxicities include
56
aminoglycoside-induced ototoxicity, Stevens-Johnson syndrome, and toxicity secondary to nitrofurantoin.

Another important consequence of the use of antibiotics is the
development of resistance. Resistance to antibiotics is a major
public-health problem and antibiotic use is being increasingly
recognised as the main selective pressure driving this resistance. Prescription of antibiotics in Europe varies greatly: the
highest rate was in France and the lowest was in the
Netherlands (700). A shift from the old narrow-spectrum antibiotics to the new broad-spectrum antibiotics is being seen.
Higher rates of antibiotic resistance are found in high consuming countries, probably related to this higher consumption.
7-3 Other medical management for rhinosinusitis
Standard conservative treatment for ARS and CRS is based on
short or long-term antibiotics and topical steroids with the
addition of decongestants - mostly in a short term regimen and
for the acute attack itself. Many other types of preparations
have been investigated, but substantial evidence for their benefit is poor. These medications include antral washings, isotonic/hypertonic saline as nasal douche, antihistamines, antimycotics, mucolytic agents/phytomedical preparations,
immunomodulators/immunostimulants and bacterial lysate
preparations. For selected patients with CRS and gastroesophageal reflux, the impact of antireflux treatment on sinus
symptom scores has been studied. Topical nasal application of
furosemide and capsaicin have also been considered in the
treatment of nasal polyposis and prevention of recurrence.
7-3-1 Decongestants
7-3-1-1 Acute rhinosinusitis
Nasal decongestants are applied in the treatment of ARS in
order to decrease congestion and in the hope of improving better sinus ventilation and drainage and symptomatic relief of
nasal congestion. Experimental trials on the effect of topical
decongestants by CT (701) and MRI scans (702) on ostial and
ostiomeatal complex patency have confirmed marked effect on
congestion of inferior and middle turbinates and infundibular
mucosa, but no effect on ethmoidal and maxillary sinus
mucosa. Experimental studies suggested beneficial anti-inflammatory effect of xylometazoline and oxymetazoline by
decreasing nitric oxide synthetase (703) and anti-oxidant action
(704)
. In contrast to previous in vitro trials on the effect of decongestants on mucociliary transport, a controlled clinical trial (II)
by Inanli et al. suggested improvement in mucociliary clearance in vivo, after 2 weeks of oxymetazoline application in
acute bacterial rhinosinusitis, compared to fluticasone, hypertonic saline and saline, but it did not show significant improvement compared to the group where no topical nasal treatment
was given, and the clinical course of the disease between the
groups was not significantly different.(705). This is in concordance with previous randomized controlled trial in adult acute
Supplement 20
maxillary sinusitis (Ib), which did not prove significant impact

of decongestant when added to antibiotic treatment in terms of
daily symptoms scores on headache and obstruction and sinus
x-ray scores, although decongestant and placebo were applied
through a bellow, which should have enabled better dispersion
of the solution in the nasal cavity (706). Decongestant treatment
did not prove superior to saline, when added to antibiotic and
antihistamine treatment in a randomized double-blind placebo-controlled trial for acute paediatric rhinosinusitis (Ib) (707).
However, a double blind, randomized, placebo controlled trial
demonstrated a significant protective effect of 14-day nasal
decongestant (combined with topical budesonide after 7 days)
in the prevention of the development of nosocomial maxillary
sinusitis in mechanically ventilated patients in the intensive
care unit (708). Radiologically confirmed maxillary sinusitis was
observed in 54% of patients in the active treatment group and
in the 82% of the controls, respectively, while infective maxillary sinusitis was obseved in 8% and 20%, respectively (708).
Clinical experience, however, supports the use of topical application of decongestants to the middle meatus in ARS but not
by spray or drops (evidence level IV).
7-3-1-2 Chronic rhinosinusitis without nasal polyps
The use of decongestants for adult CRS has not been evaluated
in a randomized controlled trial. Decongestants and sinus
drainge did not prove to be superior to saline in chronic paediatric maxillary sinusitis in terms of subjective or x-ray scores (709).
7-3-1-3 Chronic rhinosinusitis with nasal polyps
CT studies before and after decongestant application in
patients with nasal polyposis did not show any densitometric
changes in the sinuses or polyps, only decongestion of the
inferior turbinates (710). A randomized double blind placebo
controlled trial did not show any difference between placebo,
epinephrine and naphazoline on polyp size at endoscopy and
lateral imaging (711).
7-3-1-4 Side effects of decongestants
The most frequent adverse event related to topical nasal
decongestants is rebound nasal congestion in patients with
prolonged treatment or overuse of vasoconstrictive topical
medications. The effect occurs due to tachyphylaxis after 5 to 7
days of medication use. Shorter duration of decongestion and
rebound effect results in increased daily dose and may lead to
rhinitis medicamentosa (712). Significantly greater nasal reactivity, compared to placebo, was demonstrated after few weeks of
nasal decongestant.
Major adverse effects are more related to systemic decongestants, ranging in severity from tremor and headache to individual reports of stroke, myocardial infarction, chest pain,
seizures, insomnia, nausea and vomiting, fatigue, and dizziness. There are even some case reports reporting on similar
side effects of topical decongestants, especially in patients with
increased cardiovascular risks (713-716).
7-3-2 Mucolytics
Mucolytics were used as adjuncts to antibiotic treatment and
decongestant treatment in ARS in order to reduce the viscosity
of sinus secretion. The benefit of such treatment has not been
evaluated in many trials. In paediatric rhinosinusitis, a RCT
(Ib) did not prove bromhexine superior to saline in inhalation
for children with CRS (717). A second RCT (Ib) suggested
bromhexine was superior to placebo (718).
7-3-2-2 Chronic rhinosinusitis
A cohort study in a mixed group of 45 ARS and CRS patients
suggested beneficial effect of adding mucolytic to standard rhinosinusitis treatment in terms of reducing treatment duration
(719)
(evidence level III).
7-3-2-3 Nasal polyps
No clinical trials have tested the effect of mucolytics in nasal
polyp treatment.
7-3-3 Antihistamines, cromones
The beneficial effect of loratadine in terms of symptom reduction for the treatment of ARS in patients with allergic rhinitis
was confirmed in a multicentre randomized double-blind, placebo controlled trial (Ib)(720). Patients receiving loratadine as an
adjunct to antibiotic treatment suffered significantly less sneezing and obstruction on daily VAS scores, and overall improvement was confirmed by their physicians. Cromolyn did not
prove better than saline in a RCT (Ib) for treatment of acute
hyperreactive sinusitis measured by subjective scores and ultrasound scans, leading to 50% improvement in both groups (721). A
RCT (Ib) for acute paediatric rhinosinusitis did not confirm any
benefit of oral antihistamine-nasal decongestant drops (707).
Although generally not recommended as rhinosinusitis treatment, an evaluation study of CRS treatment in the USA
revealed antihistamines as rather often presribed medication in
patients with CRS (an average of 2.7 antibiotic courses; nasal
steroids and prescription antihistamines 18.3 and 16.3 weeks,
respectively, in a 12-month period) (722). However, no evidence
of beneficial effects of antihistamine treatment for CRS is
found, as there are no controlled trials evaluating such treatment.
Cetirizine in a dose of 20 mg/day for three months, significantly reduced sneezing, rhinorrhoea and obstruction compared to
placebo in the postoperative treatment of recurrent polyposis
but with no effect on polyp size (Ib) (723).
57
7-3-3-4 Antihistamines
Unlike first generation antihistamines, where central nervous
system and peripheric muscarinic side effects are significant,
frequency of side effects in newer second generation antihistamines is low. The most commonly reported events during
treatment with second generation antihistamines were upper
respiratory tract infection, wheezing, vulvitis, cough, headache,
migraine, drowsiness, sedation and injury, most of them
reported in 1 to 5% of the treated population, however, not
necessarily related to medication. Although caution with cardiotoxicity and potential for interaction with drugs metabolised
by the hepatic cytochrome P450 system, applied to older nonsedating antihistamines (like terfenadine or astemizole), this
risk seems to be absent in newer compounds (desloratadine,
levocetirizine, fexofenadine), at least in recommended treatment regimens.
7-3-4 Antimycotics
Antimycotics are used as topical and systemic treatment, as an
adjunct to sinus surgery, in allergic fungal, and invasive fungal
rhinosinusitis, especially in immunocompromized patients (724).
Surgery is considered the first line treatment for allergic fungal
(725)
and invasive fungal rhinosinusitis (726). Although the use of
antimycotics in the treatment of allergic fungal rhinosinusitis
has not been tested in controlled trials, high dose postoperative itraconazole, combined with oral and topical steroids in a
cohort of 139 patiens with AFS reduced the need for revision
surgery rate to 20.5% (727). The state-of-art treatment for invasive
fungal sinusitis is based on small series of patients and case
reports, which do not meet the criteria for meta-analysis and
may be considered as level IV evidence.
No controlled trials for antimycotic treatment for ARS was
found on the Medline search.
The fungal hypothesis, based of the premise of an altered local
immune (non-allergic) response to fungal presence in
nasal/sinus secretions resulting in the generation of chronic
eosinophilic rhinosinusitis and nasal polyposis (148), has led to
idea of treating CRS with and without NPs with a topical
antimycotic. Although the presence of fungus in sinus secretions was detected in a high proportion (< 90%) of patients
with CRS, as well as in a control disease-free population in a
few study centres (148, 149), it cannot be taken as proof of aetiology. Until recently a few case studies (level IV) had been conducted (728, 729). Ponikau et al, in a group of 51 patients with CRS,
including polyposis patients, treated patients with topical
amphotericin B as nasal/sinus washing, without placebo or
other control treatment. The treatment resulted in 75% subjective improvement and 74% endoscopic improvement (728). As
the authors stated, antifungal treatment should be evaluated in
a controlled trial to be justified.
58
Supplement 20
In a recent small randomized, placebo-controlled, doubleblind, trial using amphotericin B to treat 30 patients with CRS
with or without NP Ponikau et al (730) were also not able to
show significant effect on symptomatology although did show
a reduced inflammatory mucosal thickening on both CT scan
and nasal endoscopy and decreased levels of intranasal markers for eosinophilic inflammation in patients with CRS (a significant difference in the reduction of eosinophil derived neurotoxin (EDN), but not Il-5). The study by Weschta et al(731) did
not reveal difference between amphotericin B and placebo
treatments in the reduction of eosinophil cationic protein and
tryptase, and no difference was found between cellular activation markers whether fungal elimination was achieved or not
(for patients where fungal elements were detected), which supports the hypothesis that fungi are innocent bystanders and not
the trigger for inflammatory (presumably eosinophil) cells activation (731). Both trials used antimycotic solutions high above
minimal inhibitory concentration for fungal elimination.
However, the Ponikau trial used nasal lavage twice daily for 6
months (with significant endoscopic improvement after 3 and 6
months), while Weschta et al used nasal spray 4 times daily for
3 months. While difference in drug application and small sample size left the question of treatment success and different
objective outcomes between the trials open, a multicentre randomized, placebo-controlled, double-blind, trial (156), in 120
patients (80% with polyps) using nasal lavage for 3 months and
confirmed no benefit with amphotericin B added to nasal
lavage compared with placebo lavage in the treatment of CRS
with and without NPs. No difference between amphotericin B
and placebo was found in terms of subjective and objective
measures of improvement, i.e. mean VAS score , Sf-36,
Rhinosinusitis Outcome Measure-31 (RSOM-31), endoscopy
scores , SF-36, PNIF and polyp scores. Patients on placebo
improved in total VAS, postnasal drip VAS, rhinorrhea VAS in
non-asthma subgroup; PNIF deteriorated significantly on
amphotericin B, though did not in those on placebo (156).
Oral antifungal treatment with high dose terbinafine for 6
weeks in a randomized, placebo-controlled, double-blind,
multi-centre trial, also did not find any subjective or objective

benefit after antifungal treatment, comparing outcomes in 53
adult patients with CRS (732). No difference was found in CT
scores improvement, sinus symptom scores and therapeutic
evaluation, and confirmed the previous findings by Weschta et
al that the presence of fungi in nasal mucus (fungus positive in
41/53 patients) made no difference to treatment outcomes (732).
7-3-4-3 Nasal polyposis
Another case study (as the previous trials also included
patients with nasal polyposis) combined topical steroid treatment with amphotericin B in 74 patients with nasal polyposis
for 4 weeks (733) and found 48% disappearance of the polyps at
endoscopy in previously endoscopically operated patients.
In a double blind randomized placebo controlled trial in 60
patients with CRS with nasal polyps, topical treatment with
amphotericin B was not superior to saline in CT scores (p 0,2)
and subjective scores, which were (significantly) worse in
active treatment group (731) .
A recent open randomized trial, comparing protective effects
of lysine aspirin (LAS) and LAS combined with amphotericin
B on nasal polyp recurrence in patients who underwent medical (depot i.m. steroid) or surgical polypectomy, suggested that
adding amphotericin B to lysine aspirin in a long-term topical
treatment may add benefit in terms of recurrence protection
(734)
.Recurrence after 20 months was found in 13/25 patients
treated with LAS after surgery, in 15/25 after medical polypectomy and LAS , while 5/16 after surgical polypectomy and 7/23
after medical polypectomy protected with LAS and amphotericin B, respectively. Fungi were detected in 8/39 patients in
LAS+ampho B treated groups, and in none of 50 only LAS
treated patients. Low fungal detection indicate that the presumed protective effect of amphotericin B, added to LAS treatment may not be due to antifungal effect but the complexities
of this study make any conclusions difficult(734).
Table 7-11. Treatment with antimycotics in chronic rhinosinusitis

study
indication
treatment
number
duration
symptoms
objective
level of
evidence
Weschta, 2004
NP
amphotericin B spray
vs placebo 4 times
daily
60
8 weeks
significantly worse on
amphotericin B
no difference on CT,
endoscopy, ECP and
tryptase in lavage
Ib (-)
CRS + NP
amphotericin B lavage
vs. placebo twice
daily
30
6 months
no difference
CT less mucosal
thickening and EDN,
but not Il-5 in lavage
for active treatment
Ib (+ only
for CT)
CRS
625mg/ day oral terbinafine vs. placebo
53
6 weeks + 9
week follow up
no difference in
symptoms and RSDI
patient and physician
no difference in CT,
MRI, endoscopy
Ib (-)
CRS + NP
amphotericin B lavage
vs. placebo
116
3 months
no difference
no difference in
polyp scores, PNIF,
RSOM-31, SF-36
between groups
Ib (-)
(731)
Ponikau, 2005
(730)
Kennedy, 2005
(732)
Ebbens, 2006
(156)
59
7-3-4-4 Side effects of antimycotics

Adverse events reported after long-term oral antimycotic treatment most frequently are nausea, headache, skin rash, vomiting, abdominal pain and diarrhoea. Major adverse events, like
serious liver disfunction is rare, and mostly seen in patients at
risk and due to drug interactions.
Frequency of adverse events during 3 to 6 months topical
amphotericin B treatment in 3 randomized placebo controlled
trials was similar in the active and placebo groups. However,
major adverse events were more common in the active treatment group (9% in active vs. 0% in placebo group respectively)
although only 1 was judged to be drug-related (asthma attack).
Oral treatment with terbinafine for 6 weeks did not induce
more adverse events than placebo, none were drug-related,
and no difference in liver function was observed between
active and placebo group after 6 weeks.
The effect of amphotericin B on sinus mucosa may be explained
by some other modes of action. In common with other polyene
antibiotics and antimycotics, amphotericin B acts on cellular
membrane permeability, which may reduce the size of nasal
polyps by reducing oedema, leading to subjective improvement
(735)
. These studies were not placebo controlled and had short
observation periods. Amphotericin B is a cytotoxic drug and longterm topical application may have systemic effect. On the other
hand, nasal washings with hypertonic solution (without antifungal
medication) offer up to 60% improvement (see under chapter
7-4-7 Nasal and antral irrigation - saline, hypertonic saline).
nosinusitis. The beneficial effect of antibiotic treatment is declining together with the increased microbial resistance after repeated treatments. Such patients are usually regarded as difficult-totreat, and usually unresponsive in the long-term to medical and
surgical treatment. As altered immune response is expected to be
responsible for frequent recurrence, different immunomodulators or immunostimulants have been tested in such patients. The
most common form of medications used are bacterial lysates.
Efficacy of bacterial lysate preparations (Enteroccocus faecalis
autolysate (739), ribosomal fractions of Klebsiella pneumoniae,
Streptococcus pneumoniae, Streptococcus pyogenes,
Haemophilus influenzae and the membrane fraction of Kp (740),
and mixed bacterial lystate (741) in terms of the reduction of the
number of acute relapses in CRS, the period between the relapses and need for antibiotic treatment, have been tested in multicentre, placebo controlled RCTs (Ib) (739-741).
Another concern regarding the use of amphotericin B as topical

treatment for CRS and nasal polyposis is the possibility that
widespread use may lead to resistance. Amphotericin B remains
a valuable antimycotic systemic treatment for potentially lifethreatening invasive mycoses and increased selective pressure
with topical treatment, may give rise to increase drug resistance
in common fungal pathogens, like Candida. (736-738). This is a real
possibility due to different drug distribution pattern in the sinus
cavities (some spaces have sub-therapeutic drug concentration),
and, in time we may lose valuable antimycotic systemic drug,
which still demonstrates low resistance.
7-3-5 Bacterial lysate preparations
Altered local (and systemic) immune response to bacterial infection (antigens) may be responsible for frequent recurrence of rhi-

Bacterial lysates were tested in the treatment of acute recurrent
rhinosinusitis and the outcomes measured were the reduced rate
of acute episodes and antibiotic treatment. Enteroccocus faecalis
autolysate treatment for 6 months in 78 patients (3x30 drops
daily) resulted in 50 relapses during 6 months treatment and 8
months follow-up compared to 79 placebo treated group with 90
recurrences. The time interval to the first relapse was clearly
longer in the active arm (513 days) compared with placebo (311
days)(739). A RCT of the effect of 6 months treatment with ribosomal fractions of Klebsiella pneumoniae, Streptococcus pneumoniae,
Streptococcus pyogenes, Haemophilus influenzae and the membrane fraction of Kp was compared to placebo in 327 adult
patients (168 active and 159 placebo treatment) with recurrent
acute infectious rhinitis (the criteria for recurrent rhinosinusitis
was based on symptoms 4.3 episodes per year) demonstrated
39% reduction of antibiotic courses and 32% of days with antibotics during the 6 months treatment period(740).
Six months treatment with mixed bacterial lystate was tested
in a multicentre randomized double-blind placebo-controlled
trial in 284 patients with CRS (diagnosed by persistent nasal
discharge, headache, and x-ray criteria). Reduction in symptom
scores and over-all severity score, including cough and expectoration were significant during the treatment period (741).
Table 7-12. Treatment with bacterial lysates in chronic rhinosinusitis

study
indication
treatment
number
duration
symptoms
objective
level of
evidence
Habermann, 2002 (739)
recurrent ARS
Enterococcus
faecalis
157
6+8 months
reduced acute
episodes
50 vs. 90 recurrences, 513

vs. 311 days to first relapse
Ib
Serrano, 1997 (740)
recurrent ARS
Ribomunyl
327
6 months
reduced acute
episodes
39% reduction in antibiotic

courses and 32% days on
antibiotics
Ib
Heintz, 1989 (741)
CRS
Bronchovaxom
284
6 months
improved upper and lower

airways
no of patients with total

x-ray opacification drop 54
to 9 active vs. 46 to 25 on
placebo
Ib
60
7-3-5-3 Nasal polyposis

No data could be found on treatment with bacterial lysates in
nasal polyposis.
7-3-6 Immunomodulators/immunostimulants
Treatment with filgrastim, recombinant human granulocyte
colony stimulating factor, was tested in a RCT (Ib) in a group
of CRS patients refractory to conventional treatment, which
did not confirm significantly improved outcomes after such
expensive treatment (572). A pilot study (III) with interferon
gamma suggested this treatment may be beneficial in treating
resistent CRS, but the number of patients was not adequate to
provide evidence to justify such treatment (742). Certain groups
of antibiotics may be regarded as immunomodulators, like
quinolones (743) and macrolides (744).
7-3-7 Nasal and antral irrigation (saline, hypertonic saline)
A number of randomized controlled trials have tested nasal
and antral irrigation with isotonic or hypertonic saline in the
treatment of acute and chronic rhinosinusitis. Although saline
is considered as a control treatment itself, patients in these randomized trials were assigned to different modalities of application of saline or hypertonic saline, or hypertonic compared to
isotonic saline. The results between the groups were compared. Most of them offer evidence that nasal washouts or irrigations with isotonic or hypertonic saline are beneficial in
terms of alleviation of symptoms, endoscopic findings and
HRQL improvement in patients with CRS. Hypertonic saline is
preferred to isotonic treatment for rhinosinusitis by some
authors in the USA, mostly based on a paper indicating it signifcantly improves nasal mucociliary clearance measured by
saccharine test, in healty volunteers (745).
A randomized trial (Ib) by Adam et al (746) with two controls,
compared hypertonic nasal saline to isotonic saline and no
treatment in 119 patients with common cold and ARS (which
were the majority). Outcome measures were subjective nasal
symptoms scores (congestion, secretion, headache) at day-3,
day-8-10 and the day of symptom resolution. Rhinosinusitis
patients (98%) were also treated with antibiotics. There was no
difference between the groups and only 44% of the patients
would use the hypertonic saline spray again. Thirty-two percent
noted burning, compared with 13% of the normal saline group.
Antral irrigation (Ib) did not offer significant benefit when added
to standard 10-day antibiotic treatment in (4 antibiotics+ decongestants vs. antral washouts; 50 patients per group) ARS, demonstrating approximately 5% better cure rate in each group for
washouts than for decongestants, which was not significant (747).
A randomised controlled trial (RCT) by Bachmann (Ib), comparing isotonic saline and EMS solution (balneotherapeutic
Supplement 20
water) in the treatment of CRS in a double-blind fashion

revealed improvement in both groups, with no difference
between them (748). In the 7-days follow-up, nasal air flow was
not improved significantly. Subjective complaints, endonasal
endoscopy, and radiology results revealed a significant improvement in both groups (P = 0.0001). A similar RCT by Taccariello
et al (Ib),with a longer follow-up confirmed that nasal washing
with sea water and alkaline nasal douche produced benefit over
standard treatments. Douching per se improved endoscopic
appearances (p = .009), and quality of life scores (p = .008)
(749). These measures did not change in a control group (n =
22) who received standard treatment for CRS, but no douche.
There were significant differences between the two douching
preparations - the alkaline nasal douche improved endoscopic
appearances but did not enhance quality of life, whereas the
opposite was true for the spray. Rabago et al. (Ib) tested benefit
from daily hypertonic saline washings compared to standard
CRS treatment (control) for 6 months in a RCT using subjective scores instruments: Medical Outcomes Survey Short Form
(SF-12), the Rhinosinusitis Disability Index (RSDI), and a
Single-Item Sinus-Symptom Severity Assessment (SIA).
Experimental subjects reported fewer 2-week periods with
sinus-related symptoms (P <.05), used less antibiotics (P <.05),
and used less nasal spray (P =.06) (750). On the exit questionnaire
93% of study subjects reported overall improvement of sinusrelated quality of life, and none reported worsening (P <.001);
on average, experimental subjects reported 57 -/+ 4.5%
improvement measured by Medical Outcomes Survey Short
Form (SF-12), the Rhinosinusitis Disability Index (RSDI), and
a Single-Item Sinus-Symptom Severity Assessment (SIA). A
double blind RCT (Ib) compared the effect of nasal wash with
hypertonic saline (3.5%) versus normal saline (NS) (0.9%) for
the 4 weeks in treatment of paediatric CRS using cough and
nasal secretions/postnasal drip as subjective and a radiology
score as objective outcome measures (751). Hypertonic saline
demonstrated significant improvement for all the scores (13/15
for cough, 13/15 postnasal drip, 14/15 x-ray scores), while saline
improved only postnasal drip.
A recent double blind randomized controlled trial in 57 patients
with CRS , with minimum persistence of symptoms for 1 year
and previously unsuccesufully treated with conventional medical treatment, demonstrated significantly better improvement
after nasal lavage for 60 days with hypertonic Dead sea salt
(DSS) solution compared to conventional hypertonic saline, in
terms of rhinosinusitis symptoms scores and rhinoconjunctivitis
quality-of-life scores which was attributed to the presence of
magnesium and other oligominerals known to have an effect in
nskin conditions.(581). Similar results were found in a recent
case trial in 31 patients with resistant CRS. (752).
A randomized controlled clinical trial of nasal washing with
normal saline, hypertonic buffered saline and no treatment in
60 patients after endoscopic sinus surgery did not prove any of
the treatment superior. Hypertonic saline induced greater discharge during the first 5 postoperative days and increased pain
61
scores, compared to normal saline and no treatment, However,

no objective evaluation was done in this trial (753).
often reported. However, randomized controlled trial comparing isotonic and hypertonic saline for ARS or common cold
reported significantly higher rate of nasal irritation for hypertonic saline (32% vs. 13% for saline, respectively), while dry
nose was more common in patients using saline (36%), than in
those using hypertonic saline (21%) (746).
Uncommon side effects were nausea caused by drainage, burning, cough, drowsiness and tearing. Interestingly, side effects of
HS were less common in the treatment of CRS (6 months):
nasal irritation, nasal burning, tearing, nosebleeds, headache,
or nasal drainage were reported by 23% of the subjects, 80% of
those who reported side effects, regarded them as not significant (750).
Comparison of treatment with antral washouts in the treatment of chronic adult (754) and paediatric rhinosinusitis (755) did
not prove benefit from such treatment. In a RCT by Pang et al.
patients received either antral washouts followed by antibiotics
and topical nasal steroids or antibiotics and topical nasal
steroids alone. In each group 51.6 per cent and 50 per cent of
patients respectively improved with treatment (754).
Instead of using saline or hypertonic solution, a few non-controlled pilot trials in a small number of patients analyzed the
effect of active medication used intrasinusally. A trial in 12
patients was done using N-chlorotaurine, an endogenous oxidant with antimicrobial properties against bacteria and fungi.
The intrasinusal application of N-chlorotaurine was done 3
times a week, during 4 weeks (12 applications) using a Yamik
catether and improvement of symtpoms was found in 75 to
90% of patients, however, no improvement was found on the
sinus CT scans, before and after the treament (756).
Although saline washes are frequently recommended postoperatively, level I evidence to support this is lacking.
Nasal saline has been used as a control treatment in trials on
nasal polyposis with topical steroid, but there are no controlled
trials on saline/hypertonic saline treatment alone in nasal polyposis.
7-3-7-4 Side effects
Side effects of saline, hypertonic saline nasal washings are not
7-3-8 Capsaicin
Capsaicin, the active substance from red hot chilli pepppers, is
a neurotoxin which depletes substance P with some other neurokinins and neuropeptides, leading to long lasting damage of
unmyelinated axons and thinly myelinated axons when repeatedly applied to the respiratory mucosa. Substance P was found
effective in reducing nasal symptoms after cumulative topical
applications in the treatment of non-allergic hyperreactive
rhinitis, probably acting as desenzitizer of nasal mucosa due to
depletion of SP and neurokinins.The hypothesis that neurogenic inflammation may play a role in the pathogenesis of
nasal polyps has led to trials on capsaicin treatment of nasal
polyposis.
7-3-8-1 Acute and chronic rhinosinusitis without nasal polyps
No trials of treatment of acute or chronic rhinosinusitis with
capsaicin could be found.
Table 7-13. Nasal irrigation (saline, hypertonic saline, Dead sea solution, balneotherapeutic water) randomized controlled trials
study
indication
solution
number
duration
symptoms
objective
level of
evidence
Adam, 1998 (746)
ARS
saline vs. HS
vs. NT
119
10 days
no difference
not done
Ib
Bachmann, 2000 (748)
CRS
saline vs. EMS
40
7 days
improved, no
difference saline
vs EMS
endoscopy, plain
X-ray improved
Ib
Taccariello, 1999
CRS
sea water vs.

Alkaline vs. NT
62
30 days
improved
endoscopy, HRQL Ib
improved
Rabago, 2002 (749)
CRS
HT vs. NT
76
6 months
improved
significantly less
antibiotics, nasal
sprays
Ib
Shoseyov, 1998 (751)
CRS in children
saline vs. HS
40
4 weeks
HS all symptoms
improved, saline
PND only
x-ray improved
after HS
Ib
Friedman, 2006 (581)
CRS
HS vs.
DSS
57
2 months
DSS significantly
improved, better
than HS
DSS - HRQL
significantly
improved
Ib
Pinto, 2006 (753)
CRS after ESS
saline vs. HS
vs. NT
60
5 postop. days
higher discharge
and pain in HS
group
not done
Ib
Legend. HS: hypertonic saline; DSS: DeadaSea salt solution; NT: no treatment; ESS: endoscopic sinus surgery; HRQL: health related quality of life.
62

A case study (III) by Filiaci et al. has demonstrated significant
reduction in the size of nasal polyps after five (weekly) topical
applications of capsaicin (30 mmol/L) solution in patients with
nasal polyposis (757) . The authors noted increased nasal
eosinophilia after the treatment, which was not correlated to
the polyp size. A case study by Baudoin et al. has demonstrated significant reduction of sinonasal polyposis after 5 consecutive days treatment with increasing doses (30-100 mmol/L) of
topical capsaicin in massive polyposis measured by CT scans at
entry and after 4 weeks (III) (758). ECP in nasal lavage was not
influenced by the treatment. Protection of polyp recurrence
following endonasal surgery by 5 topical applications of capsaicin in 51 patient after surgery with a 9 months follow-up has
confirmed significant recurrence protection and significantly
better nasal patency in the active group in a randomized, double blind, placebo controlled trial (Ib) by Zheng et al (759). The
authors used 70% ethanol 3x10-6E ml capsaicin solution, which
may explain the high rate of recurrence in the control group
after ESS, which received only 70% ethanol. They noted 40%
polyp stage 0 (Malm) and 45% stage 1 in the active treatment
group, while controls demonstrated 45% stage 2 and 40% stage
3 polyposis following treatment at 9 months observation. The
low cost of capsaicin treatment was noted as a certain advantage compared to other postoperative treatments. As capsaicin
is NF kappa B antagonist in vitro, some other modes of action
may be proposed (760).
7-3-8-3 Side effects
The most common side effect following nasal capsaicin application, if not previously topically anaesthetized, is severe burning sensation in the nose and lips, and lacrimation. However,
previous topical nasal anaesthaesia with 10% xylocaine spray in
placebo-controlled trial completely blinded the active treatment (761). In the trials of nasal capsaicin treatment for idiopathic rhinitis, some other side effects were reported: dyspnoea,
headache, cough, epistaxis, dryness of nasal mucosa and exanthema (762, 763).
7-3-9 Furosemide
The protection of the hyper-reactive response to different challenges (propranolol) (764); metabisulphite (765); and exercise (766) in
asthmatics was demonstrated after inhalation of furosemide,
suggesting bronchoprotective effects, similar to the effect of
cromones.
No trials of treatment of acute or chronic rhinosinusitis with
furosemide have been found.
Protection against nasal polyp recurrence following surgery
with 1-9 years follow-up, comparable to the effect of the topical
steroid, was demonstrated after topical application of
Supplement 20
furosemide in 97 patients postoperatively versus mometasone

furoate in 33 patients, in a prospective non-randomized controlled trial (IIa) by Passali et al (767), which had been previously
reported by the same group in a case study. Relapses were
recorded in 17.5% in the furosemide, 24.2% in the mometasone
and 30% in the no treatment group, suggesting that
furosemide, as a much cheaper medication than steroids,
might be considered as a prophylaxis to polyp recurrence.
A recent randomized controlled trial compared the effect of
short term pre-operative treatment with oral methylprednisolone (1mg/kg) versus inhalation of 10 ml of 6.6 mmol
furosemide solution in 40 patients with nasal polyposis. Both
were effective but no difference was found between the two
treatment modalities after 7-day treatment, in terms of polyp
size reduction on endoscopy, nasal symptom scores (except for
olfaction, which was better in steroid group) and intraoperative
bleeding. Histological analysis of the polyps at surgery suggested a strong anti-inflammatory effect of oral steroid (in terms of
eosinophil count reduction), while furosemide treatment
demonstrated only an effect on oedema (768).
Randomized placebo-controlled trials, especially long term
treatment, are however lacking.
7-3-10 Proton pump inhibitors
Numerous trials during the past decade indicated an association between extraoesophageal reflux and airway disease, and
beneficial effect of PPI treatment on upper airway symptoms,
including some symptoms of CRS, was suggested., Postnasal
drip, a relevant CRS symptom, was established as one of the
symptoms responding to PPI treatment. However, sensation of
postnasal drip (PND)was confirmed in groups of patients with
idiopathic rhinitis, without evidence of rhinosinusitis, and in
patients without rhinitis and sinusitis.(769), and greater exposure
to gastric acid was demonstrated in patients with PND than in
the controls. As PPI treatment reduces acidity, it is a dilemma
if PPI acts on rhinitis, rhinosinusitis or sensation of PND.
Most reviews on current evidence on the association between
reflux and sinus disease advocate higher quality of controlled
trials on both etiology and treatment, in pediatric and adult
population. As PPI treatment of extraoesophageal reflux disease (like laryngitis) is based on long-term high-dose regimen,
potential side effects should be considered.
There are no trials with proton pump inhibitors for ARS.
There is no evidence for benefits in the general population suffering from rhinosinusitis following treatment with proton
pump-inhibitors, although subjective improvement was noted
in patients with laryngopharyngeal reflux (proved by pHmetry) and rhinosinusitis. Grade C evidence for a positive
association between gastroesophageal reflux and rhinosinusitis
was found in a meta analysis of the literature for this co-mor-
63
bidity (57 articles screened, 14 articles included) (770, 771)). A number of case trials of rhinosinusitis, especially paediatric (770), have
tested the efficacy of anti-reflux treatment with proton pump
inhibitors on the clinical course and symptoms of rhinosinusitis. Increased rates of reflux were detected in CRS in adults
unresponsive to standard treatment (772, 773). Further research is
expected in this field, and such treatment should be justified
by randomized controlled trials.
Non-controlled trials, especially in children, indicate the effect
on some symptoms of rhinosinusitis, presumably postnasal
drip and cough. However, a recent meta-analysis of randomized controlled trials of outcomes of the treatment of non-specific cough with proton pump inhibitors confirmed that it is
insufficient evidence to definitely conclude that reflux treatment with PPI is universally beneficial for cough associated
with reflux in adults. The beneficial effect was only seen in
sub-analysis and its effect was small (774).
Results of these studies indicate that there is a need for (larger)

controlled trials of antileukotriene treatment in CRS with or
without NP.

There are no data on proton-pump inhibitors in nasal polyposis.
7-3-11 Antileukotrienes
Leukotrienes are upregulated in asthma and nasal polyposis,
especially in aspirin- sensitive disease.
No trials were done on the antileukotrienes treatment in ARS.
7-3-11-2 Chronic rhinosinusitis and nasal polyps
Open studies suggest that antileukotrienes might be of benefit in nasal polyposis (775-777).
Antileukotriene treatment in 36 patients with CRS with or
without NP, added to standard treatment, resulted in statistically significant improvement in scores for headache, facial
pain and pressure, ear discomfort, dental pain, purulent nasal
discharge, postnasal drip, nasal congestion and obstruction,
olfaction, and fever. Overall improvement was noted by 72% of
the patients and side-effects occurred in 11% of the patients (778).
In a selected group of 15 ASA triad patients, addition of
antileukotriene treatment resulted in 9/15 with sinusitis experiencing improvement and over-all benefit in 12/15 patients,
which was confirmed by endoscopy (779). In a group of patients
with nasal polyposis, significant subjective improvement in
nasal symptoms occurred in 64% aspirin tolerant patients and
50% aspirin sensitive patients Significant improvement in peak
flow occurred only in aspirin tolerant patients, while acoustic
rhinometry, nasal inspiratory peak flow and nitric oxide levels
did not change (777). A prospective double blind comparative
study on 40 patients compared the effects of the leukotriene
receptor antagonist, montelukast and beclomethasone nasal
spray on the post-operative course of patients with sinonasal
polyps. No significant differences were found between these
two post-operative treatments in the year after surgery (780).
7-3-12 Aspirin desensitization

No controlled trials of aspirin desensitization treatment for
acute and chronic rhinosinusitis were found.
7-3-12-2 Chronic rhinosinusitis and nasal polyps with aspirin
intolerance
Systemic aspirin desensitisation or topical lysine-aspirin treatment (the only truly soluble form of aspirin) may be implicated in protection against chronic rhinosinusitis with nasal polyposis recurrence.
Sixty-five aspirin-sensitive patients with aspirin sensitive asthma underwent aspirin challenge, followed by aspirin desensitization and daily treatment with aspirin over 1 to 6 years (mean,
3.1 years). There were significant reductions in numbers of
sinus infections per year and an improvement in olfaction.
Numbers of sinus and polyp operations per year were significantly reduced and doses of nasal corticosteroids were significantly reduced. There were reductions in hospitalizations for
treatment of asthma per year and reduction in use of systematic corticosteroids (781-783).
Nucera et al. have followed three groups of patients with nasal
polyposis (about 50% aspirin sensitive), the first with 76 consecutive nasal polypectomy patients who had a topical lysineacetylsalicylate-therapy afterwards, the second 49 patients with
40 mg triamcinolone retard (medical polypectomy) and also
further lysine-acetylsalicylate-therapy and the third with 191
control patients who underwent only polypectomy but
received no placebo. The group treated with lysine-acetylsalicylate postoperatively had a recurrence rate of 6.9% after l year
and 65% after six years postoperatively, while controls experienced recurrence in 51.3% at l year and 93.5% at six years after
the operation, indicating a significant protection against recurrence from the lysine-acetylsalicylate treatment. Systemic corticoid therapy and nasal lysine-acetylsalicylate-therapy resulted
in 33% with unchanged polyp size after three years compared
to 15% in the operated-not treated group, but this was not statistically significant (784).
A case controlled trial of treament with lysine aspirin to one
nostril and placebo to the other in 13 patients with bilateral
nasal polyposis resulted in delayed polyp recurrence and 8
remained symptom free at 15 months observation period,
which was significantly better than results of the patients previously treated with steroid for recurrence protection. Endoscopy
and acoustic rhinometry indicated minor polyp size on the
aspirin treated side (785).
64
Supplement 20
Table 7-14. Other medical management for rhinosinusitis. Results from the treatment studies summarised
acute
chronic without nasal polyps
chronic with nasal polyps
treatment
study
level of
evidence
clinical
importance
study
level of
evidence
clinical
importance
study
evidence
clinical
importance
decongestant
1 RCT, 1 CT
Ib (-)
no.
no trial
none
no
no
none
no
trial
mucolytic
2 RCT
Ib (one +,
one -)
no
1 cohort
III (-)
no
no trial
none
no
phytotherapy
1 RCT
Ib
no
1 CT
Ib
no
no trial
none
no
immuno-modulator
no trial
none
no
1 RCT
Ib (-)
no
no trial
none
no
antihistamine
1 RCT allergic
Ib
yes (in allergy only)
no trial
none
no
1 RCT allergic
Ib
yes (in allergy only
antileukotriene
no trial
none
no
1 cohort
III
no
3 cohort
III
no
proton pump
inhibitor
no trial
none
no
3 cohort
III
no
no trial
none
no
lysine aspirin
desensitisation
no trial
none
no
no trial
none
no
1 RCT
2 CT
Ib
yes
furosemide
no trial
none
no
no trial
none
no
1 RCT
1 CT
Ib (-)
yes
capsaicin
no trial
none
no
no trial
none
no
1 RCT
Ib
no
anti-Il-5
no trial
none
no
no trial
none
no
1 RCT
Ib (-)
no
A double blind, randomized, placebo controlled trial did not

demonstrate any effect on nasal airway using 16mg of intranasal
lysine aspirin every 48 hours, compared to placebo treatment,
in aspirin sensitive patients, after 6 months treatment (786).
Outcomes included subjective symptom scores, acoustic rhinometry, PNIF and PEF. However, final outcomes were
analysed in only 11 available patients, and pathohistologic
analysis revealed significant decrease of CylLT 1 receptor in the
turbinate mucosa of the patients with active treatment, compared to placebo, so further trials were suggested.However,
addition of intranasal lysine aspirin in doses up to 50mg daily to
routine therapy reduced polyp size and did not adversely affect
asthma (Ogata N, Darby Y, Scadding G. Intranasal lysineacetylsalicylate (LAS) adminsitration decreases polyp volume in
patients with aspirin intolerant asthma. J Laryngol Otol 2007 in
press). The mechanisms of desensitisation probably involve
reduction of leukotriene receptors (392).
7-3-13 Phytopreparations
Treatment of rhinosinusitis by alternative medicine, including
herbal preparations is common in the general population. A
study by interview in a random telephone sample population
suffering from CRS and asthma revealed that 24% were taking
herbal preparation (787). Lack of randomized controlled trials
comparing such treatment to standard medication in rhinosinusitis patients should be a concern to health care providers.
A standardized myrtol oil preparation was proven superior to
other essential oils, and both were superior to placebo in a
RCT for uncomplicated ARS. A need for antibiotic treatment
after myrtol was 23%, compared to 40% for placebo (788).

With Andrographis paniculata in a fixed combination, Kan
Jang showed significantly improved nasal symptoms and
headache in ARS compared to placebo (789)
Guaifenesin, a phytopreparation known for its mucolytic properties, was tested in a RCT on a selected population of HIV
patients with CRS, demonstrating 20% higher improvement in
subjective scores compared to placebo in this population (790).
No controlled trials on nasal polyp treatment with phytopreparations were found.
7-3-14 Anti-Il-5 antibodies
The first small study using humanized mouse anti-IL-5 antibodies in patients with nasal polyps (791) showed no significant
treatment effect. However it indicated that local IL-5, but not
IL-5 receptor concentrations, predicted the clinical response.
7-3-15 Conclusion
The results are summarized in the next table.
7-4 Evidence based surgery for rhinosinusitis
7-4-1 Introduction
In this chapter, systematic reviews on sinus surgery efficacy in
CRS are first presented, followed by a description of comparative
trials of sinus surgery with medical treatment. The role of various
surgical modalities is then briefly reviewed, and reports on the
65
effects of concomitant diseases on sinus surgery outcomes are

detailed. There is evidence that CRS with and without polyps are
distinct subgroups of chronic inflammatory diseases of the upper
airway mucosa (see chapters 2 to 4). Approximately 20% of
patients with CRS develop nasal polyps (792), which may predispose to less favourable results of sinus surgery (793, 794).
Accordingly, reviewed articles are grouped into CRS without
polyps and CRS with polyps, when the authors differentiated
between these two subgroups. Except for a few reports on limited sinus surgery in recurrent ARS (795), sinus surgery is generally
restricted to chronic rhinosinusitis (CRS). Therefore, currently
available data do not suffice to judge the role of surgery in acute
or acute recurrent rhinosinusitis. For surgical interventions in
complications of ARS see chapter 8, for paediatric sinus surgery
see chapter 9, for a detailed description of complications of sinus
surgery refer to chapter 7, and for postoperative medical treatment please refer to chapter section 7-1-5.
case series. Patients judgement of outcome using an unbalanced three item verbal rating scale was employed. (804). A very
good result was defined as complete resolution of symptoms or
less than 2 rhinosinusitis episodes per year, a good result was
improvement but without complete resolution of symptoms or
2-5 sinusitis episodes per year, and a poor result was no
improvement or deterioration. Articles reporting a total of 1,713
patients were evaluated. Subjectively, 63% of patients reported a
very good result, 28% a good result, and 9% an unsatisfactory
result. Twelve percent of patients required revision surgery and
complications occurred in 1.6% of patients. With 1.5%, bleeding
was most the most common complication (level IV).
In a systematic review, 12 case series of endoscopic sinus
surgery were evaluated and compared with 6 case series of
conventional techniques (797). In patients with CRS with or without polyps, overall success rates ranging from approximately
70% to 90% after sinus surgery were reported. Revision surgery
was reported in 7% to 10%. If reported, complications were
below 1% (level IV).
In a recent meta-analysis, the impact of endoscopic sinus
surgery on sinus symptoms and quality of life was evaluated in
adults after failed medical treatment (803). Articles dealing with
both or not differentiating between CRS with and without
polyps were included. Forty-five of 886 screened articles were
included for full review. The reasons for exclusion were not
detailed. Of the included articles, 1 article qualified for level II
evidence, 42 for level IV evidence and 2 for level V evidence.
The authors conclude that there is substantial level IV evidence with supporting level II evidence that endoscopic sinus
surgery is effective in improving symptoms and QoL in adult
patients with CRS.
In a recent Cochrane review, 3 randomized controlled sinus
surgery studies were included(796). The authors conclude that
FESS, as practiced in the included trials, is not superior to
medical treatment with or without sinus irrigation in patients
with CRS.
It is difficult to generalise about sinus surgery studies because

surgery is indicated in selected patients who are not sufficiently responsive to medical treatment. Moreover, only a few publications on sinus surgery qualify for evidence based evaluation
(796)
and frequently studies included in systematic reviews are
assigned low evidence levels (797-799) This is in part due to specific
problems in conducting surgical trials. In general, surgery is
difficult to estimate or standardize, particularly in multi-centre
trials, and the type of treatment is difficult to conceal (blinding). Randomization may pose ethical problems unless narrow
inclusion criteria are set (514). Low budget investigator initiated trials not monitored by professional clinical research organisations are the rule.
In addition, a variety of confounders make it difficult to obtain
homogenous patient groups with comparable therapeutic procedures for unbiased evaluation of sinus surgery outcomes.
Possible relevant surgical factors include whether an external
or endonasal approach is chosen, whether a functional or conventional surgical procedure is selected, if the extent of the
surgical intervention is limited, extended or radical, and what
kind of instruments are employed. Patient dependent factors
include age, extent and duration of disease, previous surgery,
presence of polyps, concomitant diseases such as ASA-intolerance, asthma, or cystic fibrosis, and particular aetiologies
including dental, autoimmune, immune, and fungal disease
(800-803). Moreover, mode and duration of pre- and post-operative drug therapy may alter the outcome.
7-4-2 Effectiveness of sinus surgery and comparison with medical
treatment
7-4-2-1 Systematic reviews and outcomes research on sinus
surgery effectiveness
Several reviews did not differentiate between CRS with and
without polyps such as Terris and Davidson who analysed 10
7-4-2-1-1 CRS without polyps

In 2000 the Clinical Effectiveness Unit of the Royal College of
Surgeons of England conducted a National Comparative Audit
of the Surgery for Nasal Polyposis and Chronic Rhinosinusitis
covering the work of 298 consultants working in 87 hospital
sites in England and Wales (521). Patients undergoing sinus
surgery were prospectively enrolled and followed up in this
observational study at 3, 12 and 36 months post-operatively
using the SNOT-22 as the main outcome measure. One third
(952)
of the 3128 patients participating in this study had CRS
without nasal polyps and 2176 suffered from CRS with polyps.
Outcomes are reported separately for the two rhinosinusitis
subgroups. CRS-patients without polyps less frequently suffered from concomitant asthma and ASA-intolerance, had less
previous sinonasal surgery, their mean CT score was lower and
their mean SNOT-22 symptom score was slightly higher than
that of CRS patients with polyps. All forms of sinus surgery
66
were considered though the majority were performed endoscopically. Overall there was a high level of satisfaction with
the surgery and clinically significant improvement in the
SNOT-22 scores were demonstrated at 3, 12 and 36 months.
Revision surgery was indicated in 4.1% at 12 months and 10.4%
at 36 months (Level IIc).
In addition to this outcomes research study, 2 recent case
series are also presented to supplement outcome data on CRS
without polyps. In a retrospective analysis, 123 patients with
CRS without nasal polyps who underwent primary FESS with
a minimum 1-year follow-up period were evaluated (793).
Outcome parameters included the Sino-Nasal Outcome Test
(SNOT-20) questionnaire, the Lund-Mackay CT-scoring system, and the need of revision surgery. SNOT-20 scores were
26.5 preoperatively with significant improvement to 5.1 at 6
months and 5.0 at 12 months postoperatively (85% improvement) (level IV). In a case series of 77 patients with CRS without polyps, symptom and endoscopy scores were followed
between 3 and 9 years after FESS (805). Saline douches and nasal
steroids were postoperatively administered as required. After
at least 3 years, more than 90% of the patients reported symptom improvement of 80% or more. Revision surgery was performed in 15%. At the end of the follow up period, 5 patients
(7%) received nasal steroids.
7-4-2-1-2 CRS with polyps
Within the framework of the NHS R&D Health Technology
Assessment Programme, the clinical effectiveness of functional
endoscopic sinus surgery to treat CRS with polyps was
reviewed. The authors screened 444 articles and evaluated 33
articles published between 1978 and 2001 (806). Major reasons for
exclusion were the narrative character of the publication or
less than 50 patients with polyps. The authors reviewed 3 RCT
comparing functional sinus surgery with Caldwell Luc or conventional endonasal procedures (n=240), 3 non-randomized
studies also comparing different surgical modalities (n=2699)
and 27 case series (n=8208). Consistently, patients judged their
symptom improved or greatly improved in 75 to 95 percent
(level IV). The percentage of overall complications was 1.4%
for FESS compared to 0.8% for conventional procedures.
Two thirds (2176) of the 3128 patients participating in the
National Comparative Audit had CRS with nasal polyps (521).
CRS patients with polyps had no longer duration of disease, no
higher previous steroid treatment, nor ratings of their general
health before surgery than CRS patients without polyps.
Irrespective of extent of surgery, clinically significant improvement in the SNOT-22 scores were demonstrated at 3, 12 and
36 months. Polyp patients benefited more from surgery than
the chronic rhinosinusitics without polyps. Revision surgery
was indicated in 3.6% at 12 months and 11.8% at 36 months.
Major complications were rare (Level IIc).
In this context, a case series study of CRS patients with particularly extensive polyposis is worth mentioning (807). Of the 118
patients reviewed, 59 (50%) had asthma, and 93 (79%) had doc-
Supplement 20
umented allergy. All patients received extensive bilateral nasal

polypectomy, complete anterior and posterior ethmoidectomy,
and maxillary sinusotomy. One hundred (85%) also had frontal
or sphenoid sinusotomy. Follow-up ranged from 12 to 168
(median 40) months. Despite pre- and postoperative nasal and
systemic steroid treatment in the majority of patients, 71 (60%)
developed recurrent polyposis, 55 (47%) were advised to undergo revision surgery, and 32 (27%) underwent revision surgery.
History of previous sinus surgery or asthma predicted higher
recurrence and revision surgery rates. History of allergy also
predicted recurrence and need for revision.
Conclusion: One major outcomes research study (level II) and
more than a hundred reviewed case series (level IV) with highly consistent results suggest that patients with CRS with and
without polyps benefit from sinus surgery. Major complications occur in less than 1%, and revision surgery is performed
in approximately 10% within 3 years.
7-4-2-2 Combined surgical and medical treatment vs. sole medical treatment
CRS may be cured with medical treatment alone. Moreover,
sinus surgery is almost always preceded and/or followed by
various forms of medical treatment including nasal douches,
nasal steroids, systemic steroids, and systemic antibiotics. Few
studies compared sinus surgery, which was always combined
with medical treatment, with medical treatment alone. In two
studies, CRS patients with and without polyps were not differentiated.
In a prospective trial, 160 CRS patients with or without polyps
were enrolled and treated with either medical therapy alone or
medical therapy plus endonasal sinus surgery(486). Group allocation was not randomized and the non-surgical cohort had less
males, less concomitant diseases, less polyps, and less severe
disease. Outcome parameters included the SF-36 and Chronic
Rhinosinusitis Survey (CSS) questionnaire. At follow up after
3 months, the surgically treated group improved more than the
non-surgically treated group, however, improvement was not
adjusted for pre-treatment scores (level IV).
In a prospective observational study conducted by the
Cooperative Outcomes Group for ENT of the American
Academy of Otolaryngology Head and Neck Surgery, 31 otolaryngologists enrolled 276 CRS patients with or without
polyps (808). Follow up was 207, 164 and 117 patients after 3, 6
and 12 months, respectively. Success was defined as 40% or
more improvement in a subset of the CSS. Based on judgment
of the participating physicians, 83 patients received functional
endoscopic sinus surgery and 118 patients received medical
treatment only. Surgically treated patients had a 3 times higher
chance for success than patients treated only medically
(p<0.01), however, this disproportion disappeared when corrected for baseline CSS-scores in a logistic regression approach
(level IV).
67

In a prospective, randomized, controlled trial, Ragab and
coworkers enrolled 90 patients with CRS (536). Of the 90 included patients, 55 suffered from CRS without polyps and are
reported separately. During a run in phase, all patients received
a 6-week regimen of dexamethasone-21-isonicotinate and tramazoline hydrochloride (DRS) spray and an alkaline nasal
douche. Patients who remained symptomatic after this treatment were then randomized to a medically or a surgically
treated arm. In the medically randomized group, all patients
received a 12-week course of erythromycin, alkaline nasal
douche, and intranasal corticosteroid preparations. In the surgically randomized group, FESS was performed tailored to the
extent of disease. After endoscopic sinus surgery, all patients
were prescribed a 2-week course of erythromycin, DRS spray,
and alkaline nasal douche, followed by a 3-month course of
fluticasone propionate intranasal spray. After that, topical corticosteroid spray was given as needed. Outcome parameters
included the SNOT-20, SF-36, nasal NO and acoustic rhinometry measurements. At follow up visits after 6 months and at 1
year, significantly improved outcome parameters were
observed in both treatment arms, with no significant difference
being found between the medical and surgical groups (P>.05),
except for the rhinometrically assessed total nasal volume, in
which the surgical treatment demonstrated greater improvements (Level Ib).
FESS was performed on one side while the other side

remained untouched employing a randomized prospective
matched samples design. Following surgery, intranasal steroids
were given for an additional 12 months on both sides. The
sense of smell was tested for each nostril separately. It
improved after treatment with systemic and topical steroids
without additional improvement on the operated side. Surgery
had an additional beneficial effect on nasal obstruction and
secretion that persisted over the study period. However, 25%
percent of the patients required surgery also on the yet unoperated side. The authors conclude that surgical treatment is indicated after steroid treatment, if nasal obstruction persists but
not if hyposmia is the primary symptom (Level Ib).
In the prospective, randomized, controlled trial by Ragab and
co-authors already described (536), 35 CRS patients with polyps
remained symptomatic after a 6-week intensive medical regimen and were randomized into the study. At follow up visits
after 6 months and at 1 year, both treatment arms reported significantly improved outcome parameters, with no significant
difference being found between the medical and surgical
groups (P>.05), except for the total nasal volume, in which the
surgical treatment demonstrated greater improvements (Level
Ib).
In a recent RCT, 109 patients with CRS with extensive nasal
polyps were included (587). Fifty-three patients were randomly
allocated to receive oral prednisone for 2 weeks (30 mg/day for
4 days followed by a two days reduction of 5 mg) and 56 to
undergo endoscopic sinus surgery. All patients additionally
received intranasal budesonide for 12 months. Patients were
evaluated for nasal symptoms, polyp size, and QoL employing
the SF-36 questionnaire. At 6 and 12 months, a significant
improvement in all SF-36 domains, nasal symptoms and polyp
size was observed after both medical and surgical treatment. A
significant advantage for the surgically treated group was
observed for nasal obstruction, loss of smell and polyp size 6
months after randomization and for polyp size also 12 months
after randomization (level Ib).

In an open, randomized trial, Lildholdt and co-workers included 53 patients with nasal polyps (641). All patients received nasal
steroid spray during the 12 month study period. Snare polypectomy was additionally performed in 26 patients, whereas 27
patients received an intramuscular depot betamethasone injection. After 1 year, no relevant difference in the main outcome
parameters including sense of smell, PNIF, and disease recurrence were observed (level Ib).
In a second open RCT, Lildholt and co-workers included 34
patients with nasal polyps who did not improve after participation in a preceding placebo controlled trial comparing two
doses of intranasal budesonide(493). Sixteen patients received a
single depot injection of 14 mg betamethasone and 18 patients
underwent intranasal snare polypectomy. Outcomes were
assessed after 11 months additional nasal steroid treatment and
again after 12 months without any treatment. Snare polypectomy and systemic betamethasone outcome 12 months after
treatment were remarkably similar as measured by mean nasal
improvement score, polyp score or mean score of sense of
smell (p>0.05). Within 1 year without nasal steroid treatment,
50% of the patients experienced further nasal polyps, however
the authors did not differentiate polyp recurrence by medical
or surgical treatment (level Ib).
In a study by Blomqvist and coauthors, 32 CRS patients with
polyps were pretreated with systemic steroids (prednisolone for
fourteen days) and budesonide for 4 weeks (809). Thereafter,
Conclusion: In the majority of CRS patients, appropriate medical treatment is as effective as surgical treatment. Sinus
surgery should be reserved for patients who do not satisfactorily respond to medical treatment.
7-4-3 Surgical modalities
7-4-3-1 Endonasal versus external approach
Endonasal approaches include surgical procedures performed
through the nostril, irrespective of the extent of surgery and
the kind of visualization of the surgical field. Today, endonasal
procedures are predominantly performed employing endoscopes. The most commonly performed external surgical procedures include the sublabial transfacial Caldwell Luc
approach with or without transantral ethmoidectomy and sphenoidectomy, and transfacial frontoethmoidectomy. In a few
68
studies, outcomes of external and transnasal procedures were

compared though not differentiating between CRS patients
with and without polyps.
Penttila and co-workers randomized 150 CRS patients after
failed antimicrobial therapy and antral irrigations for chronic
maxillary sinusitis to either endonasal endoscopic sinus
surgery (n=75) or an external Caldwell Luc approach (n=75).
The percent changes of symptom scores before and one year
following surgery were evaluated (Level Ib). Functional endoscopic sinus surgery revealed significant advantages in the
relief of nasal obstruction, hyposmia and rhinorrhea, but not
facial pain. Patients overall judgement and rate of complication
also significantly favoured the endonasal approach (810, 811). The
study population was re-evaluated 5 to 9 years later with 85%
of the former study participants responding to a questionnaire.
In both surgical groups, approximately 80% were asymptomatic
or distinctly improved without relevant intergroup differences
(812)
. However, postoperative cheek pain and paraesthesia were
noted in 23% of Caldwell Luc group, which is a frequent complication of this approach (813). The histopathology of maxillary
sinus specimens obtained before and 1 year after surgery from
patients of the two treatment arms of the Penttila-studies were
evaluated by Forsgren et al., indicating a greater reduction in
inflammatory parameters in the mucosa of the maxillary sinus
after the Caldwell-Luc approach (814).
In a retrospective evaluation, Unlu and coauthors randomly
selected 37 Caldwell-Luc-operated and 40 endonasally operated patients. Outcome was assessed with nasal endoscopy and
CT-scans (815). CT was normal in 12% of Caldwell-Luc-operated
patients in comparison to 75% of endosopically operated
patients. Endoscopy revealed a patency rate of the antral window in 48% Caldwell-Luc-operated and 86.7% in endonasally
operated patients. The authors conclude superiority of the
endonasal approach. (Level IV).
Videler and co-authors treated 23 CRS patients refractory to
repeated endonasal procedures, Caldwell Luc and intensive
medical treatment via an Caldwell Luc approach with removal
of the medial maxilarry wall (573). Clinical improvement was
observed the majority of patients (level IV).
No studies comparing endonasal surgery with external
fontoethmoidectomy or Caldwell-Luc approach in patients
with CRS without polyps were found.
No studies comparing endonasal surgery with external
fontoethmoidectomy were identified. In several studies,
endonasal sinus surgery was compared with the Caldwell-Luc
approach in CRS patients with polyps. In the NHS R&D
Health Technology Assessment Programme evaluation, an
overall symptomatic improvement was reported in approximately 80% after endoscopic sinus surgery and in 43 to 84%
after conventional surgery including Caldwell Luc. Disease
Supplement 20
recurrence was 8% for FESS compared to 14% for CaldwellLuc approach (806).
McFadden and co-workers evaluated the long term outcome
(up to 11 years) in 25 patients with extensive nasal polyps and
ASA-intolerance. Sixteen patients were operated via an extended endonasal approach and 9 via a Caldwell Luc approach with
radical sphenoethmoidectomy. Of the endonasally operated
patients, 6 underwent a revision surgery via a Caldwell Luc
approach whereas none of the patients who had received a
Caldwell Luc approach initially was reoperated (432).
Conclusion: Long term symptom relief in chronic sinusitis can
be obtained by the endonasal endoscopic and the CaldwellLuc approach, however, results favour the endonasal approach.
The Caldwell-Luc approach carries a higher risk of early postoperative facial swelling and infraorbital nerve irritation.
Comparative studies of endonasal versus external frontoethmoid approaches are currently not available.
7-4-3-2 Conventional endonasal surgery versus functional
endonasal sinus surgery
Conventional sinus surgery is a collective term for surgical
techniques already used before the devlopment of functional
sinus surgery. They include external approaches, maxillary
sinus irrigation, simple (snare) polypectomy, inferior meatal
antrostomy, and radical transnasal spheno-ethmoidectomy
with or without middle turbinate resection. Unlike functional
techniques, conventional sinus procedures do not proceed
along the natural pathways of sinus ventilation and mucociliary
transport revealed by the fundamental work of Messerklinger
(816). Restoring ventilation and mucociliary transport by functional surgery along the natural ostia allows recovery of the
diseased sinus mucosa, which is not resected (817, 818) .
Concurrently with the development of the functional
approach, rigid endoscopes became available, which improved
visualization during endonasal surgery. The evolving concept
of functional endoscopic sinus surgery (FESS) spread worldwide by the efforts of Stammberger and Kennedy (819, 820). In two
studies, a conventional approach was compared with functional
sinus surgery in CRS patients with or without polyps.
In a prospective controlled trial, Arnes and coauthors performed an inferior meatal antrostomy on one side and a middle meatal antrostomy in the opposite nasal cavity in 38
patients with recurrent acute or chronic maxillary sinusitis (821).
The laterality was randomized. After an observation period
ranging between 1 and 5 years, no significant side differences
in symptom scores or radiological findings were observed
(level Ib).
In a randomized controlled trial, 25 patients after functional
endoscopic sinus surgery were compared with 25 after conventional surgery. Conventional surgery included antral puncture,
intranasal ethmoidectomy, and Caldwell-Luc procedures.
Follow up ranged from 15-33 months with a mean of 19
months, at the end of which 76% of the functional group had
69
complete relief of symptoms, 16% partial relief and 8% no

relief as compared to 60%, 16%, 24% in the conventionally
treated group (822). However, this study is flawed by an elusive
method of randomization, lack of information on homogeneity
of patients groups, and high variability of procedures performed. (no level applied).
Conclusion: Functional endoscopic surgery is superior to minimal conventional procedures including polypectomy and antral
irrigations, but superiority to inferior meatal antrostomy or
conventional sphenoethmoidectomy is not yet proven.
parameters was investigated in CRS patients, not differentiating between CRS with and without polyps. In a prospective
trial, 65 CRS patients with and without polyps were randomized to undergo limited endonasal functional surgery
(infundibulectomy) and a more extensive functional procedure
including sphenoethmoidectomy and wide opening of the
frontal recess. Disease extent was similar in both treatment
arms. Outcome parameters included symptom scores,
rhinoscopy scores and nasal saccharin transport time (825). Recall
rates were below 60%. Outcome parameters revealed no relevant differences after 3, 6 and 12 months (level Ib).
Based on the concept that diseased sinus prechambers, not
small sinus ostia, are the cause for chronic sinus inflammation,
minimal invasive sinus surgery (MIST) is advocated by some
authors (826). Basically, sinus ostia are exposed during MIST, but
not enlarged. In a prospective, uncontrolled trial, Catalano and
Roffman followed 85 patients with CRS for a mean 24 months.
Changes in the CSS score served as outcome parameter and
revealed significant improvements similar to FESS studies
(level IV).
Some authors advocate partial resection of the middle
turbinate to expand the surgical approach (827), while others
modify it only in case of abnormalities and leave as much as
possible of the middle turbinate intact as a landmark in case
revision surgery is needed (817). In a retrospective evaluation
including 100 FESS patients, Giacchi and coauthors preserved
the middle turbinate on one side and partially resected it on
the other side (828). The authors observed no side differences in
the outcome parameters studied (level Ib).
In a randomized trial, 1,106 matched CRS patients with and
without polyps, who underwent similar functional endonasal
sinus surgery with (509 patients) or without (597 patients) partial middle turbinate resection (829). Partial middle turbinate
resection was associated with less synechia formation (p<0.05)
and less revision surgeries (p<0.05) than middle turbinate
preservation. Complications particularly caused by partial middle turbinate resection were not observed (level Ib).
In a prospective, randomized trial, uncinectomy was performed
in 295 patients with chronic maxillary sinusitis. In 140 patients,
a large middle meatal window (diameter > 16 mm) was either
unilaterally or bilaterally created, whereas in 140 patients small
middle meatal antral windows (diameter < 6 mm) were produced. In 170 patients, no preoperative CT was available.
Follow up visits were attended by 133 (45%) patients 12 to 38
months after surgery. Outcome parameters included patients
judgment of symptom change (absent, improved, unchanged,
worsened) and various endoscopic findings. Symptom relief,
endoscopy findings and antral window size did not depend on
the surgically created antral window diameter (830).
7-4-3-3 Extent of surgery

Extent of surgery may vary from mere uncinectomy to radical
sphenoethmoidectomy with middle turbinate resection. In several studies, the extent of sinus surgery on various outcome

No reports comparing less or more extensive surgical procedures
explicitly in CRS patients without polyps could be identified.

Eighty-nine patients with chronic sinusitis confined to the
maxillary sinus without nasal polyps were enrolled in a
prospective randomized controlled trial (823). After antibiotic
therapy for at least 4 weeks prior to inclusion, 45 patients
received sinus irrigation only and 44 patient sinus irrigation
followed by FESS. Patients were followed in regular intervals
up to one year. The per protocol analysis included 36 irrigation only and 41 irrigation and FESS patients. In 13 irrigation only patients and 2 irrigation and FESS patients, second
surgery was performed due to lack of efficacy (p<0.001).
Moreover, outcomes for purulent discharge and loss of smell
showed significant improvement in irrigation and FESS group
as compared with those obtained by sinus irrigation alone after
one years observation. Scores for other sinusitis symptoms did
not differ significantly between the groups (Level Ib).
In the NHS R&D Health Technology Assessment Programme
evaluation (806), polyp recurrence was 28% following functional endoscopic ethmoidectomy compared to 35% following
intranasal polypectomy. The percentage of overall complications was 1.4% for FESS compared to 0.8% for conventional
procedures.
Hopkins and co-workers analyzed 1848 patients with nasal
polyps, a subgroup of 3128 patients who participated in the
National Comparative Audit of Surgery for Nasal Polyposis
and Rhinosinusitis (824). The authors compared the SNOT-20
supplemented with two additional items (SNOT-22) after simple polypectomy and after more extensive surgery both largely
performed endoscopically in addition to medical treatment.
The SNOT-scores did not differ significantly between the two
treatment arms after 12 and 36 months, if adjusted for relevant
confounders. Revision surgery was carried out more frequently
in the polypectomy only group in the first 12 months after
surgery (p=0.04), but this difference was not significant at 36
months. Complication rates did not differ significantly.
70
The patency rate after large middle meatal antrostomy and

undisturbed maxillary ostium in endoscopic sinus surgery for
nasal Polyposis was compared in 60 patients with bilateral
nasal polyps and chronic maxillary sinusitis (831). A large middle
meatal antrostomy was performed on one side, whereas on the
other side an uncinectomy preserving the natural maxillary
ostium was done. The sides were chosen randomly. The patency rates of a large middle meatal antrostomy were significantly
higher 3 months after surgery when compared with undisturbed maxillary ostium. This difference became insignificant
after 12 months (level Ib).
Jankowski and co-authors retrospectively compared a case
series of 37 CRS patients with extensive nasal polyps treated
with FESS with a historical group of 36 patients with similar
disease extent treated with radical sphenoethmoidectomy and
middle turbinate resection (832). Outcome parameters assessed 5
years following surgery included a mailed questionnaire on
nasal symptoms, the number of patients with revision surgery,
and nasal endoscopy scores at a follow up visit. Recall was
below 80% and differed significantly between the two groups.
The radical surgical procedure yielded better symptom scores,
less recurrences, and better endoscopy scores at the follow up
visit (level IV).
Conclusion: In CRS patients not previously operated, extended surgery does not yield better results than limited surgical
procedures. Although not evidence based, the extent of
surgery is frequently tailored to the extent of disease, which
appears to be a reasonable approach. In primary paranasal
surgery, surgical conservatism is recommended.
7-4-3-4 Revision surgery
Approximately 10% operated patients respond insufficiently to
sinus surgery with concomitant medical therapy and eventually
require a secondary surgical procedure (833). Middle turbinate
lateralisation, synechiae and scar formation in the middle meatus, an incompletely resected uncinate process, and retained
ethmoid cells are frequent findings in patients undergoing revision surgery (834-836). Previous revision surgery, extensive polyps,
bronchial asthma, ASA-intolerance and cystic fibrosis are predictors for revision surgery (793, 801, 837-840). Inflammatory involvement of underlying bone may also be of significance (159).
Technical issues of sinus revision surgery have recently be
reported by Cohen and Kennedy (841). A more extensive surgical
procedure and also external approaches may be indicated (573, 832,
842)
. Success rates of revision endoscopic sinus surgery has been
reported to range between 50 and 70% (514, 838) (level IV).
Complication rates of revision surgery are higher when compared with initial surgery and approximate 1%, but may be as
high as 7% (833, 840).
In a case series of CRS patients without polyps, 15% were surgical revisions (805). These patients had higher CT scores before
Supplement 20
their initial surgery and also before the revision surgery than
patients undergoing primary surgery (level IV). McMains and
Kountakis reported a series of 125 patients with a follow up of
at least 2 years after revision endonasal sinus surgery (839).
Outcome parameters included the SNOT-20 and an endoscopy
score. Of these patients, 66 suffered from CRS without nasal
polyps. These patients experienced a significant improvement
of their outcome parameters comparable with the results after
primary surgery reported in other trials (level IV).
McMains and Kountakis also reported the results of 59 CRS
patients with nasal polyps after revision surgery (839). Consistent
with the results of the National Comparative Audit (824) and the
comparative study by Deal and co-workers (793), CRS patients
with polyps had lower SNOT scores preoperatively (less severe
symptoms), more previous surgeries, and a higher CT score
preoperatively than CRS patients without polyps. However, the
improvement of outcome parameters after revision surgery was
significant and comparable with the improvement in CRS
patients without polyps.
Conclusion: Revision endonasal sinus surgery is only indicated, if medical treatment is not sufficiently effective. Substantial
symptomatic improvement is generally observed in both, CRS
with and without polyps, though the improvement is somewhat less than after primary surgery. Complication rates and
particularly the risk of disease recurrence are higher than after
primary surgery. Some patients still suffer from CRS symptoms after several extensive surgical procedures. CT scans frequently show mucosal alterations adjacent to hypersclerotic
bony margins in an extensively operated sinus system. As a
rule, revision surgery is not indicated in these patients.
7-4-3-5 Instruments
In recent years, numerous instruments have been developed
for sinus surgery. Cutting forceps may improve controlled
mucosal resection and help to avoid mucosal tearing. Powered
instruments may facilitate controlled resection, particularly of
large nasal polyps. Continuous suction/irrigation of microdebriders improve visualisation of the surgical field. Moreover,
lasers have been employed for mucosal excisions and bone
ablation. Given the number of devices available, only a few
comparative studies have been published. In these reports,
CRS patients with and without polyps were not differentiated.
7-4-3-6 Cutting instruments
In a prospective double blind trial, 100 consecutive patients
were followed after endoscopic sinus surgery (843). Cutting forceps had been randomly used on one side and non-cutting forceps on the other side. Lateralised symptoms (headache, maxillary pressure, nasal obstruction and secretions) and endoscopic findings (secretion, pus, blood, crusts, oedema, polyps and
adhesions) were evaluated on both sides 1 year postoperative-
71
ly. Both types of instruments gave satisfactory healing situations. No significant difference in the global symptom and
endoscopic score between the 2 types of instruments was
found (level Ib).
preoperatively, and postoperatively on weeks 1, 4, 12 and 24.

Of the parameters assessed in the course of healing, oedema
prevailed on the laser-assisted side, while crusting was characteristic in the traditional operation site. Overall, KTP-laserassisted FESS was as effective as endonasal sinus surgery with
conventional instruments. Disadvantages of the laser-assisted
procedure included the investment for the instrument and the
additional time needed for laser surgery (level Ib).
7-4-3-7 Powered instruments

Microdebriders were initially developed for arthroscopic
surgery. They consist of a suction based powered instrument
with a blunt end and guarded inner 90 oscillating or rotating
blade, frequently supplemented with a device for irrigation.
Cutting and removing only tissue suctioned into the instrument opening while blood and tissue debris are removed by
suction/irrigation, they provide excellent control and precision
of soft tissue resection (844).
In a retrospective case series study, a group of 250 patients
undergoing surgery with a microdebrider was compared with a
group of 225 patients undergoing endoscopic sinus surgery
with conventional instruments (845). The assignment of patients
to each group was arbitrary and non-random, with the majority
of the standard technique patients being treated earlier in the
study. The use of the microdebrider demonstrated faster healing with less crusting than standard techniques, as well as
decreased bleeding, synechia formation, lateralization of the
middle turbinate, and ostial reocclusion (level IV).
In a prospective randomized trial, 24 CRS patients were treated
with microdebriders on one side and with conventional instruments on the other side (846).The authors were unable to
demonstrate an advantage of mechanical debriders over conventional instrumentation (level Ib).
Hackman and Ferguson reviewed both, positive and negative
tissue effects secondary to powered instrumentation (844). The
authors conclude that microdebriders will continue to advance
the field of endoscopic surgery, providing clearer operative
fields and causing less tissue trauma in experienced hands.
However, their literature review also illustrates the potential
severity of complications, when orbital and cerebral contents
are rapidly aspirated by the powered instrument (no level
applied).
7-4-3-8 Laser
In a randomized controlled trial, outcomes for holmium-YAG
assisted sinus surgery were evaluated in 32 patients with CRS
undergoing ESS (847). Following a randomization plan, one side
was operated with conventional instruments and the contralateral side with laser. The use of holmium-YAG laser in ESS
resulted in significantly lower blood loss during surgery and
less post-operative crust formation than conventional ESS, but
long term subjective outcomes did not show significant differences between the methods (level Ib).
In a similar experimental setup, the application of KTP lasers
in endoscopic sinus surgery was investigated in 24 patients (848).
Laser-assisted FESS was performed on one side and FESS
with conventional instruments on the other side. Patient symptoms were recorded using a self-administered questionnaire
Conclusion: Laser assisted endonasal surgery, powered instruments or sharp forceps offer some advantages over conventional instruments but may be associated with some particular
risks. Currently, there is no evidence that they improve sinus
surgery outcomes.
7-5 Influence of age concomitant diseases on sinus surgery outcome
7-5-1 Sinus surgery in the elderly
Previous survey data ranks rhinosinusitis the sixth most common chronic condition of elderly persons, occurring more frequently than cataracts, diabetes and general visual impairment
(849)
. In a case series study, 56 CRS patients between 61 and 80
years old were followed after functional endoscopic sinus
surgery with nasal endoscopy and the SNOT-20 (849). Outcomes
were comparable to reports from younger patient populations,
no severe complication occurred (level IV). In a retrospective
case control study, functional endonasal sinus surgery outcome in 46 CRS patients >65 years were compared with 522
CRS patients who were 18-64 years old (850). In the elder patient
group, complications occurred significantly more frequently
than in the younger patients group. In particular orbital complication were frequently observed in the elder patient group
(level III). Jiang and Su retrospectively compared complication
rates of 171 CRS patients elder than 65 years with 837 adult
patients and 104 patients younger than 16 years. They found
that the geriatric group experienced a disproportionately larger
share of operative complications. Outcomes were similar in all
three groups (851).
Conclusion: CRS is a common condition in the elderly.
Reported sinus surgery outcomes do not differ from a younger
patient population. However, higher surgical complication
rates were found in 2 reports. Moreover, general anaesthesia
bears higher risks and the capacity to recover from a severe
surgical complication such as a CSF leak may be impaired.
7-5-1-1 Asthma
Bronchial asthma is frequently associated with CRS with and
without polyps and may have influence on sinus surgery outcomes. A trend for more severe sinus disease in CRS patients
with concomitant asthma without aspirin intolerance has been
reported by Kennedy (514). Clinically, CRS patients with polyps
and asthma have higher CT-scores, more severe nasal obstruction and hyposmia, and more severe asthma, while CRS
72
patients without polyps and asthma experience more severe

headache and postnasal discharge (852). Investigations of concomitant asthma on sinus surgery outcomes in CRS patients
with or without nasal polyps yielded inconsistent results (853).
Concomitant asthma was associated with worse postoperative
endoscopy findings in two retrospective analyses (801, 803), but had
no independent influence on other outcome parameters (level
IV). Consistently, symptom scores improved significantly in
both asthmatics and non-asthmatics postoperatively, but asthmatics exhibited significantly worse postoperative endoscopic
outcomes in 21 asthmatic compared with 77 non-asthmatic. No
difference was found in other outcome parameters between
the two groups (854) (level IV)
In 3 other studies on various predictors of treatment success of
sinus surgery, asthma had no independent influence on outcome parameters (514, 802, 855).
Concomitant asthma is frequent in patients with sinusitis without polyps. In a retrospective evaluation, 13 of 73 CRS patients
without polyps had also asthma. However, concomitant asthma did not influence sinus surgery outcomes in this study (805).
In a case series studies, Dunlop and coworkers followed the
course of 50 CRS patients with bronchial asthma after sinus
surgery (852). In this group, 16 CRS patients without polyps had
concomitant asthma. Their sinusitis symptoms improved significantly following sinus surgery (level IV).
In a prospective outcome analysis, 79 patients underwent
endoscopic sinus surgery for CRS with polyps (853). In a subgroup of 22 CRS patients with concomitant asthma, more
recurrences and less symptom score improvement was
observed (level IV). In the study by Dunlop and coworkers
described above (852), 34 CRS patients with polyps and concomitant asthma revealed improved sinus symptoms 1 year
after sinus surgery (level IV).
Conclusion: Currently there is no evidence that CRS patients
with asthma benefit less from sinus surgery than patients without asthma concerning their CRS symptoms.
7-5-2 Effect of sinus surgery on bronchial asthma
The incidence of self reported rhinosinusitis in asthma patients
was recently evaluated employing the data of two major asthma trials (856). Self reported rhinosinusitis was associated with
bronchial asthma in 70% of the 2500 study participants.
Asthma patients with concomitant rhinosinusitis had more
asthma exacerbations, worse asthma symptoms, worse cough,
and worse sleep quality. The question, how sinus surgery and
medical CRS treatment may alter the course of bronchial asthma, was reviewed by Lund (857) and Scadding (858). The authors
describe the somewhat intricate base of evidence and conclude
that the weight of evidence suggests a beneficial effect. Studies
Supplement 20
published thereafter support this view. However, once again,

authors did not differentiate between CRS with and without
polyps.
In a follow up analysis of long term results of functional
endonasal sinus surgery, 72 of 120 patients answered a questionnaire. A subgroup of 30 patients with CRS and asthma
were analysed (859). On average 6.5 years post surgery, asthma
symptom improvement, less asthma attacks, less inhaler and
less oral steroid use were reported by the majority of patients
(level IV).
Park and co-authors retrospectively evaluated the data of a
subgroup of 79 of 134 sinus surgery patients with asthma (860)
with a questionnaire. Improved asthma was noted by 80% of
the patients (level IV)
In a controlled study, 15 patients with CRS and asthma underwent endoscopic sinus surgery and 6 patients, who rejected
surgery, were treated with nasal steroids only (861). The authors
compared peak expiatory flow (PEF) and oral steroid consumption 6 months before and after treatment. In the surgically treated patients, mean PEF improved 9845 l/min (p<0.005)
whereas no change was observed in the medically treated
group. Oral steroid consumption was reduced in 7 surgically
treated patients, remained unchanged in 2 and increased in 2
and was not nedded before and after surgery in 4 patients
(level IV).
In a retrospective medical record analysis 13 patients with
chronic bronchial asthma who underwent FESS and received
comprehensive asthma care before and after FESS (mean, 19.3
and 33.1 months, respectively) were included. Outcomes comprised pre- and post-FESS individual and group mean asthma
symptom scores, medication use scores, pulmonary function
test results, and emergency department visits or hospital
admissions for asthma (862). Following FESS, there was no statistically significant change in group mean asthma symptom
scores, asthma medication use scores, pulmonary function test
results, and the number of emergency department visits or
hospital admissions (level IV).
In a case series study, 50 CRS patients with concomitant asthma were included (852). Twelve months after endoscopic sinus
surgery, 40% noted asthma improvement, 54% stated that there
was no difference and 6% thought their asthma control was
worse. Inhalant steroids could be reduced by 20%, and were
taken at the same dose as preoperatively by 64%. However,
oral steroid consumption was reduced significantly (p<0.001)
and hospital admissions for asthma were less frequent in the
year after surgery than in the year before (p<0.025, level IV).
Dhong and co-authors followed the clinical course of 19
patients with CRS and asthma who underwent ESS for rhinosinusitis (863). They observed a significant improvement in diurnal
and nocturnal asthma symptoms and asthma medication
scores. Pulmonary function tests did not change (level IV).
Ragab and co-workers report a prospective evaluation of a subgroup of 43 asthma patients (864) joining a randomised trial comparing the effects of sinus surgery and medical treatment in
73
CRS patients with and without polyps (865). Outcome parameters

included asthma symptoms, control, forced expiratory volume
in one second (FEV1), peak flow, exhaled nitric oxide, medication use and hospitalisation at 6 and 12 months from the start
of the study. Overall asthma control improved significantly following both treatment modalities, but was better maintained
after medical therapy, where improvement could also be
demonstrated in the subgroup with nasal polyps. Medical treatment was superior to surgery with respect to a decrease in
exhaled nitric oxide and increase in FEV1 in the polyp
patients. Two patients noted worsening of asthma post-operatively. Treatment of chronic rhinosinusitis, medical or surgical,
benefits concomitant asthma; that associated with nasal polyposis benefits more from medical therapy (level Ib).
nasal steroid non-responders demonstrated a significant

decrease of their spirometry values at T1 (p < 0.05) and at T2
(p < 0.0005), whereas no significant change was observed in
nasal steroid responders. BHR did not significantly change
over the 4-yr follow-up period in the two groups. No change in
pulmonary symptoms and/or asthma severity occurred.
Although asthma may accompany chronic rhinosinusitis with

and without polyps, several studies particularly addressed
lower airway effects of sinus surgery in CRS patients with
polyps. In a prospective outcome analysis, 79 patients underwent endoscopic sinus surgery for CRS (853). Twenty-eight
patients with asthma symptoms were assessed before and after
surgery, using peak flow (liter/second) and medication scores
Patients showed improvement in terms of their asthma symptoms, peak flow and medication score. (level IV).
Palmer and co-workers retrospectively reviewed the charts of a
subgroup of 15 CRS patients with steroid dependent asthma
selected from a group of 75 consecutive CRS patients with asthma who underwent endoscopic sinus surgery (866). Outcome parameters included the number of days and total dose of oral prednisone and antibiotics in the year before and after sinus surgery.
Fourteen of the 15 patients meeting study criteria decreased their
postoperative prednisone requirement by total number of days
(preoperative 84 versus postoperative 63 days (p < 0.0001).
Postoperatively, patients required an average of 1300 mg less oral
prednisone (p < 0.033). Antibiotic use also decreased (p < 0.045),
with an average use of antibiotic nine weeks preoperatively
versus seven weeks postoperatively (level IV).
In a prospective trial, Lamblin and co-workers included 46
CRS patients with polyps and concomitant bronchial asthma
(n=16) or non-symptomatic bronchial hyperresponsiveness
(n=30). Outcome parameters measured at baseline (T0), after 1
year (T1) and after 4 years (T2) included nasal symptom
scores, various spirometry values and a bronchial carbachol
challenge (867). All patients were treated first with nasal steroids
for 6 weeks (beclomethasone 600 microg/d). Eighteen patients
were successfully treated with nasal steroids (nasal steroids
responders) and medical CRS treatment was continued without sinus surgery. In 28 patients who did not improve with
nasal steroids (nasal steroids non-responders), intranasal shenoethmoidectomy was performed in addition to continued
nasal steroid treatment. At baseline, clinical characteristics of
nasal steroid responders and non-responders -including the
frequency of Samters triad- did not reveal significant differences. Despite combined surgical and medical CRS-treatment,
Conclusion: Apparently, various confounders not yet sufficiently defined influence the effects of surgical CRS treatment
on concomitant asthma. In studies published in recent years,
predominantly positive effects of surgical CRS treatment on
concomitant asthma severity were reported However, the level
of evidence is low.
7-5-2-1 ASA intolerance
Intolerance to acetylsalicylic acid derived compounds such as
aspirin or other acid NSAIDs frequently manifests as Samters
triad characterized by bronchial asthma, aspirin sensitivity, and
CRS with polyps. The majority of CRS patients with aspirin
intolerance have diffuse, extensive rhinosinusitis (514). In an
early report, poorer outcome in 11 patients with ASA-intolerance out of 120 prospectively followed patients treated with
sinus surgery was observed (514). However, when stratified for
extent of disease, ASA-intolerance did not adversely affect outcome (Level IV). In more recent trials, ASA-intolerance was
rather consistently found to adversely affect sinus surgery outcomes.
In a case series study, 80 patients with ASA-intolerance and
mostly extensive polyps were followed after sinus surgery (868).
Sinus symptoms and asthma severity improved in more than
80% of the patients. Before surgery, more than 30% were
steroid dependent due to asthma severity and less than 10%
after surgery. However, a significant incidence of revision
surgery was observed in this patient group (level IV).
A higher number of repeat operations was also observed in a
retrospective case control trial (869) including 18 patients with
and 22 patients without ASA-intolerance (level IV).
In a retrospective chart review, 17 patients who underwent ESS
with nasal polyps and steroid-dependent asthma with or without aspirin sensitivity and a minimum of 1 year postoperative
follow-up were evaluated (870). Nine patients were ASA sensitive, and eight patients were ASA tolerant. The postoperative
Lund-Mackay scores (p<0.001), the forced expiratory volume
at 1 second (FEV1, p<0.05), and systemic steroid consumption
(p<0.05) improved significantly in the 17 patients. Unlike ASA
tolerant patients, the 9 ASA sensitive patients did not have a
significant improvement in postoperative FEV1 and sinonasal
symptoms (level IV).
In a multivariate analysis of various outcome predictors,
119 adult patients with CRS were prospectively followed-up for
1.4 +/- 0.35 years after sinus surgery. ASA intolerance was the
only concomitant condition significantly worsening the outcome (519).
Conclusion: CRS patients with ASA-intolerance tend to suffer
74
from more extensive sinus disease. They benefit from sinus

surgery, but to a lesser extent than patients without ASA-intolerance. They are more prone to disease recurrence and more
frequently undergo revision surgery than ASA-tolerant CRS
patients.
7-5-2-2 Allergy and atopy
In most studies, the diagnosis of allergy was based solely on
the presence of a positive skin prick test and/or serum specific
IgE determinations. This indicates atopy, but may not suffice
to diagnose allergic rhinitis (AR), particularly persistent AR (871).
Walker and co-authors matched a cohort of 19,186 individuals
without ENT disease registered in 1988 in the U.S: Navy
Aviation Medical Data retrieval System with 678 persons with
AR as the only ENT disease (872). During the period from 1990
to 1995, physicals were identified of 465 AR cases and 12,628
controls. The incidence of chronic sinusitis in the AR group
was 5/465 compared to 30/12,628 in the control group (risk
ratio = 4.5, 95% CI 1.7 to 11.6). Consistently, the reported incidence of atopy in CRS patients ranges between 50 and 80%
which is higher than in the general population. CRS in atopic
patients appears to be more severe (60, 873-878). Atopy was equally
frequently associated with CRS with and without polyps (879).
Conversely, in patients with positive skin prick tests to house
dust mites, pathologic CT findings were significantly more frequent than in prick test negative controls (880).
In several trials not differentiating between CRS with and
without polyps, atopy interfered with sinus surgery outcome. It
was associated with less symptom improvement in one retrospective evaluation of several sinus surgery outcome predictors
(801)
, but had no relevant influence on pre- or postoperative CT
or endoscopy findings nor on QoL scores in an other evaluation (803).
However, antiallergic treatment appears to compensate for the
possible shortcomings of sinus surgery in allergic patients.
Nishioka and co-authors compared postoperative middle
meatal antrostomy patency, middle meatal synechia formation
and polyp recurrence in 211 non-allergic CRS patients and 72
CRS patients considered allergic based on clinical history, skin
prick tests and serum specific IgE (879). Of the 72 allergic
patients, 66 received an allergen specific immunotherapy either
before or after surgery. Allergic patients had a significantly
higher incidence of recurrent sinusitis, which could be reduced
by allergen specific immunotherapy. The authors conclude
that allergic patients treated with surgery and concomitant
immunotherapy do as well as non-allergic patients, whereas
allergic patients treated with surgery alone do substantially
worse (level IV).
Similarly, immunotherapy and medical allergy treatment
before surgery improved the surgical success rate at a 1 year
follow up in children with CRS from 64% to 84% (p=0,022) (881).
The latter figure was identical to the success rate in children
without allergy (level IV).
Supplement 20
A consistent finding was reported earlier by Schlenter and

Mann, who surgically treated 31 allergic and 34 non-allergic
CRS patients (882). Of the 31 allergic patients, 15 underwent concomitant allergen specific immunotherapy. Surgical outcome
was comparable in non-allergic and allergic patients after concomitant immunotherapy, but significantly worse in allergic
patients without immunotherapy, despite antiallergic medical
treatment (level IV).
In a prospective study, 24 CRS patients without polyps allergic
to perennial allergens and 82 patients with CRS without polyps
without allergy underwent endoscopic endonasal ethmoidectomy after medical pre-treatment (883). Comparing both groups,
symptom scores did not differ significantly before and 6 to 18
months after surgery.
Consistently, in a case series of 77 CRS patients without
polyps, concomitant allergy had no influence on surgical outcome (805).
In a double-blind placebo-controlled trial, 26 CRS-patients
without polyps with positive skin prick tests to house dustmite
and persistent symptoms after sinus surgery received 256
microg budesonide daily or placebo through an intubation
device into one of the maxillary sinuses for 3 weeks before
clinical assessment and a second biopsy (619). The authors found
an improvement in the symptom scores in 11 of the 13 patients
who received budesonide and a decrease in CD3 positive cells
(P = .02) and eosinophils (P = .002), and a decrease in the density of cells expressing interleukin 4 (P = .0001) and interleukin
5 messenger RNA (P = .006) after treatment.
In patients with extensive polyposis (807), allergy diagnosis predicted a worse outcome and increased recurrence rate (level
IV)
Conclusion: Allergic rhinitis may predispose to and aggravate
CRS. In several studies, positive skin prick tests and/or serum
specific IgE to inhalant allergens were associated with poorer
sinus surgery outcome, particularly in CRS with polyps. This
shortcoming can be compensated for with antiallergic treatment. After confirmation of allergy by allergic history or appropriate clinical tests, allergen specific immunotherapy apparently improves sinus surgery results in atopic or allergic CRS
patients.
7-5-2-3 Cystic fibrosis
This autosomal recessive genetic disease is characterized by
epithelial secretory dysfunction and frequently associated with
CRS. In cystic fibrosis, CRS with and without nasal polyps is
observed (884). Immunologically, CRS in cystic fibrosis (CF)
patients differs from CRS in patients without CF (425, 884).
Persistent colonisation with Pseudomonas aeruginosa is a
common finding. Vitamin K deficiency related coagulopathies
75
are also common (885). Reports concentrating on CRS in CF

patients have mainly concerned the paediatric population,
which is in part due to reduced life expectancy.
Due to underlying medical issues such as acquired coagulopathies and advanced pulmonary disease, perioperative morbidity is assumed to be higher in this group (886). In 41 patients
with CF undergoing 52 sinus surgeries performed by a single
surgeon over a 34-month period, complication occurred in
11.5%, including 2 cases of epistaxis, 1 case of periorbital
ecchymosis, and 1 case of pulmonary hemorrhage. Delayed
complications included 1 case of epistaxis and 1 case of
intranasal scarring (level IV). No increased perioperative risk
was found by others (887) (level IV).
The paranasal sinuses may act as a reservoir from where bacteria spread to the lower respiratory tract. After lung transplantation, sinus derived graft infection with Pseudomonas aeruginosa may induce a frequently lethal bronchiolitis obliterans
syndrome. In 37 patients with cystic fibrosis after lung transplantation, sinus surgery was performed and repeated sinus
aspirates and bronchoalveolar lavages were obtained for microbiological examniations. Sinus surgery was successful (three or
less Pseudomonas aeruginosa positive aspirates) in 54% and
partially successful (4 or 5 positive aspirates) in 27% of patients
(888)
. A significant correlation of bacterial growth in sinus aspirates and bronchoalveolar lavages was observed (p<0.0001).
Successful sinus management led to a lower incidence of tracheobronchitis and pneumonia (P=0.009) and a trend toward a
lower incidence (p=0.23) of bronchiolitis obliterans syndrome
(Level IV).
Functional endoscopic sinus surgery with subsequent monthly
antimicrobial antral lavages (n=32) were compared with a historic control group receiving conventional sinus surgery without postoperative lavages (n=19). CF-patients with CRS with
and without nasal polyps were included. For repeated antral
lavages, modified 19 gauge butterfly intravenous catheters
were fixed in the maxillary sinus. Conventionally operated
patients underwent one or more of the following procedures:
polypectomy, ethmoidectomy, antrostomy, or Caldwell-Luc
operation (889). The group treated with functional sinus surgery
and antral lavages had fewer operations per patient, and a
decrease in repeated surgery at 1 year (10% vs 47%) and 2 year
follow up (22% vs 72%) (level IV).
group was 2.7. The authors report improved pulmonary function, sinus symptoms, and exercise tolerance 3 months post
surgery, however, polyps recurred in all patients within 18
months (Level IV).
Rowe-Jones and Mackay performed endoscopic sinus surgery
on 46 cystic fibrosis patients with chronic, polypoid rhinosinusitis (891). Their mean age at first surgery was 237.5 years.
Follow-up ranged from 1 month to 6 years (mean, 28.2
months). Overall, 50% of the patients suffered either recurrence of preoperative severity or had to undergo second endoscopic sinus procedure (level IV).

Several reports explicitly describe CRS with polyps in CF
patients. From a cohort of 650 patients undergoing endoscopic
sinus surgery for CRS, 28 patients suffered from cystic fibrosis
(800)
. Overall subjective improvement rate in the cohort as a
whole was 91% improved, whereas 54% of the cystic fibrosis
patients derived significant benefit at six month follow-up.
(Level IV).
In a retrospective report, 8 CRS patients with polyps out of 16
adults with cystic fibrosis underwent sinus surgery (890). The
mean number of previous surgery in the surgically treated
Conclusion: CF patients frequently suffer from severe CRS, in

particular with diffuse polyps refractory to medical treatment.
Due to a tendency to recur, repeated sinus surgery is often
needed to achieve symptomatic relief. In CF patients, the
paranasal sinuses may serve as a source for Pseudomonas
aeruginosa induced lung infections. Consequent local antibiotic lavages help to prevent recurrent CRS and lung infection.
7-5-2-4 Sinus surgery in the immune compromised patient
Immune deficiency states are frequently associated with CRS
include HIV-infection, bone marrow transplantation and
humoral immondeficiencies.
7-5-2-4-1 HIV
Rhinosinusitis in the HIV-infected is an increasingly common
problem. The gradual depression of humoral and cellular
immunity, delayed mucociliary transport, nasopharyngeal lymphoid tissue hyperplasia and a tendency towards increased IgE
levels may contribute to sinusitis development. Particularly at
CD4-counts below 50 cells per mm3, Pseudomonas aeruginosa
is a common pathogen (892). Cytomegalovirus may cause sinusitis in HIV-infected patients and they have an increased risk to
develop invasive fungal sinusitis. Thus CT scans, and sinus
lavages with special stains, cytologies and cultures are required
in refractory sinusitis or patients with low CD4 counts (893). The
first line treatment of sinusitis in HIV-positive patients is medical, in refractory cases targeted to the identified organisms.
Surgical treatment is reserved for patients who do not respond
to targeted medical treatment.
Sabini and co-authors retrospectively reviewed their experience with performing endoscopic sinus surgery in 16 acquired
immune deficiency (AIDS) patients (117). At an average followup time of 16 months, 14 of the endoscopic sinus surgery
patients reported improvement from their preoperative condition (level IV).
In a retrospective case series study, 106 HIV+ patients who
underwent sinus surgery between 1987 and 1998 were evaluated (894). Between 1987 and 1991, 36 patients were treated with
minimal invasive sinus surgery just addressing the involved
sinus with only 20% clinical improvement. Since 1992, the
authors treated their HIV+ patients with more extensive
surgery including sphenoethmoidectomy, middle meatal
76
antrostomy and drainage of the frontal recess, which resulted

in a clinical improvement rate of 75%, irrespective of the CD4
counts (level IV).
In two case series, Murphy and co-workers observed the clinical outcome of 30 HIV-positive CRS patients refractory to
medical treatment (895). Outcome parameters included olfactory
tests, symptom scores, and a quality of well-being assessment.
Symptom and well-being scores improved significantly following endoscopic sinus surgery, whereas olfactory thresholds did
not improve significantly (level IV).
Patients with AIDS may develop acute invasive fungal sinusitis. If detected early, combined surgical and antifungal treatment may be beneficial (896, 897).
7-5-2-4-2 Bone marrow transplant
Bone marrow transplantation (BMT) is a frequent cause of
acquired immune deficiency. Both, cellular and humoral
immunity are impaired. Particularly allogeneic BMT requires
intense immunosuppression to allow initial engraftment and to
prevent graft versus host disease. Allogeneic BMT is associated
with acute and chronic CRS in approximately 40% (898). Sinus
micobiology was investigated in 18 BMT patients who developed sinusitis evaluating 41 microbiologcal specimens
obtained by antral puncture and nasal swabs from the middle
meatus (899). Agents most commonly isolated were gram-negative bacteria including Pseudomonas aeruginosa and Searratia
marescens. Gram positive bacteria were isolated in 27%.
Various fungi were isolated in 16% of the specimens.
Micorbiological results of antral punctures and nasal swabs
were consistent in 5 of 41 specimens.
Kennedy and co-workers report on 29 bone marrow transplant
recipients with documented invasive fungal infections of the
sinuses and paranasal tissues (1.7% of 1692 bone marrow transplants performed). All patients received medical management,
such as amphotericin, rifampin, and colony-stimulating factors,
in addition to surgical intervention (900). Surgical management
ranged from minimally invasive procedures to extensive resections including medial maxillectomies. The mortality rate from
the initial fungal infection was 62%. Twenty-seven percent
resolved the initial infections but subsequently died of other
causes. Prognosis was poor when cranial and orbital involvement and/or bony erosion occurred. Extensive surgery was not
superior to endoscopic functional surgery (level IV).
Sinus surgery was performed in 28 of 311 bone marrow transplant patients retrospectively evaluated (901). No fungal sinusitis
was observed. An aggressive surgical approach yielded a high
mortality rate whereas limited surgical approaches with intensive postoperative care proved appropriate (level IV).
7-5-2-4-3 Non-acquired immunodeficiencies
Patients with humoral immunodeficiencies including common
variable immunodeficiency, ataxia telangiextasia, or X-linked
agammaglobulinaemia are at increased risk to develop CRS (902905)
. In patients with CRS refractory to medical and surgical
Supplement 20
treatment, non-acquired immune deficiencies may affect

humoral, cellular, and frequently both immune response pathways. Chee and co-workers selected 79 out of 316 patients with
CRS with and without polyps, who suffered from severe CRS
refractory to medical treatment (114). Fifty-seven patients had
undergone one or more previous sinus surgeries.
Approximately 30% of the 79 included patients suffered from
decreased T-cell function and approximately 20% had some
form of immunoglobulin deficiency. Common variable immunodeficiency was diagnosed in 10%. Accordingly, in a high number of patients with long lasting rhinosinusitis, humoral deficiencies were identified, particularly of the IgG3-subclass (906, 907).
However, in unselected patients with sinus fungus ball, CRS
with and without polyps, humoral deficiencies were not more
frequent than in the general population (908). Recently, the relevance of isolated immunoglobulin or IgG subclass deficiencies
has been challenged and vaccine response to protein and capsular polysaccharides has been suggested superior to assess
humoral immune function in CRS patients (909-912). One publication reporting on sinus surgery results in 11 patients with
humoral deficiencies was identified (913), and resolution of sinus
symptoms was observed in 5 of 9 evaluable patients under concomitant IV immunoglobulin therapy (level IV).
Conclusion: IN HIV-positive patients, three case series suggest
beneficial effects of sinus surgery refractory to medical treatment. In patients sinusitis before or after bone marrow transplantation and in non-acquired immunodeficiency syndromes,
current data to judge the role of sinus surgery are insufficient.
7-6 Complications of surgical treatment
7-6-1 Introduction
After the introduction of endoscopic sinus surgery, the indication for operations in this region expanded, the number of
operators increased together with an increase in the numbers
of operations, but also increasing the absolute number of iatrogenic complications. As a consequence, for a period of time in
the United States, paranasal sinus surgery was the most frequent source of medicolegal claims (914).
7-6-2 Complications of sinus surgery
Factors responsible for complications are the variability of the
anatomy of this region, the proximity of the brain and orbita
and last but not least the ability of the operator to maintain
orientation especially in revision surgery.
The typical complications are listed in table 7-15.
7-6-3 Epidemiology of complications of sinus surgery using nonendoscopic techniques
The following table presents the number of complications in
several studies using non-endoscopic sinus surgery.
7-6-4 Epidemiology of complications of sinus surgery using endo-
77
minor complication rates, with

for example more synechiae
being seen in endoscopic
surgery, could be a result of
the more precise follow-up
using an endoscope, as compared to follow-up with anterior rhinoscopy. On the other
hand ecchymosis was not
always considered a complication in the pre-endoscopic
period.
Table 7-15. Complications following paranasal sinus surgery

location
minor complications
major complications
orbital
orbital emphysema
ecchymosis of the eyelid
orbital hematoma
loss of visual acuity/blindness
diplopia
enophthalmia
nasolacrimal duct damage
intracranial
CSF leak - uncomplicated
CSF leak
pneumcephalus (Tension )
encephalocoele
brain abcess
meningitis
intracranial (subarachnoid) bleeding
direct brain trauma
bleeding
small amount of bleeding

stopped with packing
no need for blood transfusion
damage to anterior ethmoidal artery

damage to sphenopalatine artery
damage to internal carotid artery
bleeding which requires transfusion
In a study by Kennedy et. al

, a survey regarding complications of sinus surgery was
other
synechiae
toxic-shock syndrome
mailed to 6969 otolaryngoloslight exacerbation of pre-existent asthma
anosmia
gists; 3933 responses (56.44%)
hyposmia
severe exacerbation of pre-exsitent
local infection (osteiitis)
asthma or broncospasm
were obtained, and 3043 of
post-FESS MRSA infection
death
these physicians (77.37%)
atrophic rhinitis
reported that they performed
myospherulosis
temporary irritation of infraorbital nerve
ethmoidectomy. Completed
hyperaesthesia of lip or teeth
questionnaires were available
for review from 42.21% of all
Academy fellows (2942 physicians). The survey confirmed that
scopic techniques
there has been a marked rise in the frequency of ethmoidectoThe following table (8.6) presents the number of complications
my and in the amount of training in ethmoidectomy since
in studies using endoscopic sinus surgery and which included a
1985. At the same time the frequency of microscopic, external
minimum of 100 patients. Meta-analysis of these data suggests
or transantral ethmoidectomy seemed to decrease. In 86% a
major complications occur in about 0.5% and minor complicapreoperative CT-scan was routinly done.
tions in about 4% of cases. In a recent prospective multicentre
The study did not demonstrate a clear and consistent statistical
study of 3,128 patients undergoing endoscopic sinus surgery,
relationship between the incidence of complications, the type
major complications occured in 0.4% of patients. Of note, the
of surgery performed, and the quality of training. Moreover,
complication rate was linked to the extent of the disease in
physicians who provided data from record review tended to
terms of symptom severity and health-related quality of life,
report higher rates than those who estimated responses. The
the extent of nasal polyps, levels of opacity of the sinuses on
majority of physicians discussed specific potential complicaCT scans and the presence of comorbidity, but not to surgical
tions with their patients before surgery and routinely percharacteristics (521).
formed preoperative computed tomography. The study
demonstrated that physicians who experienced complications
7-6-5 Comparison of various techniques
at higher rates were more likely to discuss these complications
Comparison of non-endoscopic and endoscopic techniques
with patients before surgery (76% discussed CSF leak, 63%
shows similar frequencies of complications. Differences in
(944)
Table 7-16. Epidemiology of complications following paranasal surgery, using non-endoscopic techniques
author/year
orbita
intracranial
bleeding
others
minor
Freedman and Kern, 1979 (915)
565
16
Taylor et al, 1982 (916)
284
Stevens and Blair, 1988
87
Eichel, 1982 (918)
123
no numbers
Sogg, 1989
(917)
146
Friedman and Katsantonis, 1990 (920)
1163
25
Lawson, 1991 (921)
600
Sogg and Eichel, 1991 (922)
3000
288
(919)
78
Supplement 20
Table 7-17. Epidemiology of complications following paranasal surgery, using endoscopic techniques (adapted from (923))
author/year
orbital
intracranial*
bleeding
others
minor
Schaefer et al, 1989 (924)
100
14
Toffel et al, 1989 (925)
170
Rice, 1989 (926)
100
10
Stammberger and Posawetz, 1990 (927)
500
22
Salman, 1991 (928)
118
28
Wigand and Hoseman, 1991 (929)
500
10
no numbers
Lazar et al, 1992 (930)
210
16
Vleming et al, 1992 (931)
593
38
Weber and Draf, 1992 (932)
589
20
15
no numbers
Kennedy, 1992 (514)
120
May et al, 1993
1165
94
Smith and Brindley, 1993 (933)
200
16
Dessi et al, 1994
(1105)
386
no numbers
Cumberworth et al, 1994 (935)
551
no numbers
Lund and Mackay, 1994
650
no numbers
337
34
(934)
(800)
Ramadan and Allen, 1995 (936)

Danielson and Olafson, 1996
230
10
Castillo et al, 1996 (938)
553
36
Weber et al, 1997 (939)
325
30
Rudert et al, 1997 (940)
1172
10
10
Dursum et al, 1998
(937)
no numbers
-
no numbers
415
12
12
56
Keerl et al, 1999 (942)
1500
no numbers
Marks, 1999
393
(941)
(943)
Hopkins et al, 2006 (944)

total amount
3128
14005
3
7
5
2
60
(0,40%)
65
(0,50%)
84
(0,60%)
22
-
14
(0,01%)
207
506
(3,60%)
* includes CSF leaks
meningitis, 54% permanent diplopia, 66% intraorbital

hematoma, 87% lost of vision, 46% intracranial lesions, 40%
death in relation with the operation).
overall major complication rate of 0.03% (12 major orbital complications and 22 intracranial complications in 10,000 FESS
operations).
Between 1985 and 1990 the following complication rates were

seen:
7-6-6 Risk factors for complications in sinus surgery

The risk of complications in sinus surgery depends on several
factors:
extent of the pathology (ie requiring infundibulotomy or
complete pansinus operation);
first or revision surgery (loss of landmarks, dehiscent lamina papyracea);
right- or left sided pathology (right side most often affected);
operation under local or systemic anaesthesia (feedback
from patient!);
amount of bleeding during the operation;
expertise of the operator (learning curves).
With respect to the last point, a structured training program for
beginners in sinus surgery is recommended, including cadaver
dissection, hands-on training and supervision during the first
operations.
7-6-7 Conclusion
The complication rate in this study was significantly lower in

the hands of experienced operators with 11 to 20 years experience.
In Australia Kane (945) did an similar review, presenting an
Table 7-18. Complications comparison of non-endoscopic and endoscopic techniques
technique
major
complications
no of
deaths
endoscopic ethmoidectomy
0.41%
intranasal ethmoidectomy with headlamp
0.36%
23
external ethmoidectomy
0.52%
transantral ethmoidecthomy
0.18%
79
Table 7-19. Predicitve factors of sinus surgery outcomes

Outcome parameter
RP
FP
An
Al
As
NP
Chambers 1997 (855)
questionnaire, endoscopy
182
12
u1
no
no
no
Gliklich
SF-36, CSS, endoscopy
108
Kennedy (514)
verbal rating, endoscopy
120
Kim (946)
endoscopy score
98
Marks
(486)
PO
AI
PS
-
no
no
no
no
no
u4
yes
no
no
no
no
12
no
no
no
no
yes
no
improvement score
93
12
no
yes
no
no
no
no
Marks (801)
endoscopy score
93
12
no
no
yes
no
no
no
Marks (801)
revision needed
93
12
yes
no
no
no
no
yes
Smith (803)
endoscopy score
119
12
no
yes6
0.09
no
no
no
yes7
Smith
no
yes
no
no
no
yes10
0.09
no
no
(801)
RSDI
119
12
Smith (803)
CSS
119
12
Wang (802)
CSS
230
Wang (802)
endoscopy score
230
(803)
no
no
yes
no
no
0.09
no
yes
yes
yes
yes
RP: Recall/participants; FP: Minimum follow up; An: Analysis; A: Age; S: Sex; PO: Pre-operative score; E: Extent; Al: Allergy; As: Asthma;
a
NP: Polyps; AI: Aspirin intolerance; PS: Previous surgery
1: univariate, 2: multivariate, 3: high preoperative CSS score was associated with worse outcome, 4: stratified for disease severity, 5: less symptomatic
improvement in females (p=0.008), 6: worse scores associated with more improvement, 7: associated with less improvement, 8: worse scores associated with more improvement, 9: ssociated with less improvement, 10: worse scores associated with more improvement
Sinus surgery is well established and there are several techniques used to adequately treat the pathology. Nevertheless,
the risk of minor or major complications exists and has to be
balanced with the expected result of operative or conservative
treatment. The learning curve of less-experienced operators
has to be considered, as well as the complexity of the individual case.
A preoperative CT-scan is nowadays standard in the preoperative assessment and especially important in revision surgery
where image guidance may have a role.
Figure 7-2. SNOT-22 scores in the National Comparative Audit in CRS

patients with and without nasal polyps (adapted from (521).
Figure 7-3. Forced expiratory volume in one second (FEV1) in percent

of the predicted value (y-axis) in CRS-patients with polyps and concomitant asthma (n=16) and concomitant non-symptomatic bronchial
hyperreactivity (BHR, n = 30) following CRS treatment. In 18 patients
CRS was sufficiently controlled by medical treatment only (Steroid
responsive) and 28 patients required additional endonasal surgery for
sufficient CRS control (Not steroid responsive, adapted from (867).
80
Supplement 20
8. Complications of rhinosinusitis and nasal polyps

8-1 Introduction
In the pre-antibiotic era, complications of rhinosinusitis represented extremely common and dangerous clinical events.
Today, thanks to more reliable diagnostic methods (CT, MRI)
and to the wide range of available antibiotics, their incidence
and related mortality have dramatically decreased. In some
cases however, if sinus infection is untreated or inadequately
treated, complications can still develop (947). In patients affected
by acute bacterial rhinosinusitis with intracranial spread
despite antibiotic therapy, there still is a high incidence of morbidity and mortality rate, estimated at between 5% and 10% (948).
Complications of rhinosinusitis are classically defined as
orbital, osseous and endocranial (948) though rarely some unusual complications can develop (Table 8.1) (949-953).
An extremely useful test, although not specific, is the white
cell count which, if elevated in ARS unresponsive to treatment, is highly suggestive of a complication.
8-2 Epidemiology of complications
Epidemiological data concerning the complications of rhinosinusitis vary widely and there is no consensus on the exact
prevalence of the different types of complications. Moreover,
the relationship between acute or chronic rhinosinusitis and
the various complications is not clearly defined in the literature. This is probably related to the different number and
methods of sampling patients in the various studies and no
account is taken of local demographics. For these reasons, as
Table 8-1 clearly shows, an attempt to make a comparison of
the different epidemiological data available is difficult.
For example, whilst the percentage is similar in two studies

that compared two different groups of selected patients affected with pansinusitis (72.4% and 75% respectively) (472,473), the percentage in another (955) is smaller (37%); this is probably due to
the fact that in this sample, both acute and chronic disease
were studied, whereas the other two authors focused their
attention on acute cases.
In another mixed (acute and chronic) sample, Clayman highlighted the frequency of intracranial complications in patient
with complicated rhinosinusitis as about 3.7 %, but no data concerning the global prevalence of complications were given. (959).
8-3 Orbital complications
8-3-1 Systemic
If there is a complication in rhinosinusitis, the eye is often
involved (956, 1111) espeacialy in ethmoiditis, whereas this is rare in
sphenoidal infection (961). The spread of infection directly via
the thin and often dehiscent lamina papyracea (961); or by veins
(962)
occurs with relative ease.
According to Chandlers classification orbital complications
may progress in the following steps (963):
periorbital cellulitis (preseptal edema),
orbital cellulitis,
subperiosteal abscess,
orbital abscess or phlegmon and
cavernous sinus thrombosis (947, 964).
Moreover orbital complications especially in children, often
occur without pain (965, 1106). Orbital involvement is manifested by
Table 8-1. Epidemiological data of complications in rhinosinusitis

author
country
age
pathology
pts
total % of
complications
orbital
intracranial
osseous
soft tissue
Mortimore, 1999
South Africa
adults
acute pansinusitis
87
72.4% (63/87)
Nigeria
adults
acute/chronic
pansinusitis
90
37% (33/90)
41%
5%
32%
18%
Germany
adults/
children
acute pansinusitis
36
75% (27/36)
58% (20+1/36)
11% (3+1/36)
Russia
adults
rhinosinusitis
0.8%
0.01%
USA
adults
rhinosinusitis
176
8.5% (15/176)
USA
adults
acute/chronic
rhinosinusitis
649
3.7% (24/649)
USA
children
rhinosinusitis
443
3%
(14/443)
(954)
Ogunleye, 2001
(955)
Eufinger, 2001
(956)
Kuranov, 2001
(957)
Gallagher, 1998
(958)
Clayman, 1991
(959)
Lerner, 1995 (960)
8.4%
(3/36)
81
swelling, exophthalmos, and impaired extra-ocular eye movements (966). Periorbital or orbital cellulitis may result from direct
or vascular spread of the sinus infection. As the spread of sinus
infection through the orbit follows a well-described pattern,
the initial manifestations are oedema and erythema of the
medial aspects of the eyelid. Spread of infection from the maxillary or frontal sinus produces swelling of the lower or upper
eyelid, respectively (964).
A CT scan of the sinuses with orbital sequences to distinguish

between orbital and periorbital (subperiosteal) abscess should
be performed. Evidence of an abscess on the CT scan or
absence of clinical improvement after 24-48 hours of i.v. antibiotics are indications for orbital exploration and drainage.An
ophthalmologist should check visual acuity from the early
stages of the illness and i.v. therapy should cover aerobic and
anaerobic pathogens. It can be converted to an oral preparation
when the patient has been afebrile for 48 hours (967).
8-3-2 Periorbital cellulitis

Periorbital cellulitis (inflammation of the eyelid and conjunctiva) (953) involves the tissue anterior to the orbital septum and is
readily seen on CT scan as soft tissue swelling. It is the most
common complication of rhinosinusitis in children (967) and it
manifests itself as orbital pain, blepharal oedema and high
fever (968). Periorbital cellulitis usually responds to an oral
antibiotic appropriate to common sinus organisms but if not
aggressively treated, may spread beyond the orbital septum (967).
8-3-3 Orbital cellulitis
As the inflammatory changes spread beyond the orbital septum, proptosis develops together with some limitation of ocular motion, indicating orbital cellulitis. Further signs are conjunctival oedema (chemosis), a protruding eyeball (proptosis),
ocular pain and tenderness, and decreased movement of the
extraocular muscles (953, 969).
This complication requires aggressive treatment with intravenous antibiotics.
Any children with rhinosinusitis and proptosis, ophthalmoplegia, or decreased visual acuity should have a CT scan of the
sinuses with orbital detail to distinguish between an orbital
and periorbital (subperiosteal) abscess. Both conditions cause
proptosis and limited ocular movement. Evidence of an abcess
on the CT scan or progressive orbital findings after initial i.v.
antibiotic therapy are indications for orbital exploration and
drainage. Repeated ophthalmologic examination of visual acuity should take place and i.v. antibiotic therapy may be converted into oral when the patient has been afebrile for 48 hours
if the ophthalmological symptoms and signs are resolving (967).
8-3-4 Subperiosteal or orbital abscess
The clinical features of a subperiosteal abscess are oedema,
erythema, chemosis and proptosis of the eyelid with limitation
of ocular motility and as a consequence of extra-ocular muscle
paralysis, the globe becomes fixed (ophthalmoplegia) and visual acuity diminishes.
An orbital abcess generally results from diagnostic delay or to
immunosuppression of the patient (968) with a frequency of 9%
and 8.3% (351, 970) in paediatric studies.
Blindness may result from central retinal artery occlusion,

optic neuritis, corneal ulceration, or pan-ophthalmitis. In such
a case the CT usually reveals oedema of the medial rectus
muscle, lateralization of the periorbita, and displacement of
the globe downward and laterally. When the CT scan shows
obliteration of the detail of the extraocular muscle and the
optic nerve by a confluent mass, the orbital cellulitis has progressed to an abscess, in which there is sometimes air due to
anaerobic bacteria. Sepsis not infrequently can spread intracranially as well as anteriorly into the orbit (971).
8-4 Endocranial complications
These include epidural or subdural abscesses, brain abscess,
meningitis (most commonly), cerebritis, and cavernous sinus
thrombosis (967, 972, 973).
The clinical presentation of all these complication is non-specific, being characterized by high fever, frontal or retro-orbital
migraine, generic signs of meningeal irritation and by various
degrees of altered mental state(958) while intracranial abscesses
are often heralded by signs of increased intracranial pressure,
meningeal irritation, and focal neurologic deficits (966). Although
an intracranial abscess is relatively asymptomatic, subtle affective and behavioral changes often occur showing altered neurologic function, altered consciousness, gait instability, and
severe, progressive headache.(953, 967).
Endocranial complications are most often associated with ethmoidal or frontal rhinosinusitis. Infections can proceed from
the paranasal cavities to the endocranial structures by two different routes: pathogens, starting from the frontal sinus most
commonly or ethmoid sinus, can pass through the diploic
veins to reach the brain; alternatively, they can reach the
intracranial structures by eroding the sinus bones (958).
All endocranial complications start as cerebritis, but as necrosis
and liquefaction of brain tissue progresses, a capsule develops
resulting in brain abscess. Studies show a high incidence of
anaerobic organisms or mixed aerobic-anaerobic in patients
with CNS complications.
A CT scan is essential for diagnosis as it allows an extremely
accurate definition of bone involvement, whereas MRI is
82
Supplement 20
Table 8-2. Endocranial complications in rhinosinusitis

author
Gallagher 1998
(958)
Albu 2001 (974)
number
complications
mortality/further defects
176 patients
meningitis represented 18%

cerebral abscess 14%
epidural abscess 23%
mortality 7%
morbidity 13%
16 patients
6 meningitis
6 frontal lobe abscess
5 epidural abscess
4 subdural abscess
2 cavernous sinus thrombophlebitis
Dunham 1994 (967)
subdural empyema in 18%
Eufinger 2001 (956)
together meningitis, empyema and brain abscess

constitute 12% of all the intracranial complications
mortality 40%
surviving patients often have
neurological disability
Oxford LE 2005 (1106)
18 patients
(mean age 12 y)
7 epidural abscess
6 subdural abscess
2 intracerebral abscess
2 meningitis
Germiller 2006 (1107)
25 patients
(mean age 13 y)
13 epidural abscess
9 subdural abscess
6 meningitis
2 encephalitis
2 intracerebral abscess
2 cavernous sinus trhomboplebitis
mortality 4 %
Quraishi 2006 (1108)
12 patients
(mean age 14 y)
2 frontal lobe abscess

8 subdural abscess
1 subdural abscess
mortality 8%
morbidity 16 %
Hakim 2006 (1109)
8 patients
(mean age 12 y)
1 cerebral abscess
1 cerebral infarct
3 frontal bone osteomyelitis
4 subdural abscess
4 subdural abscess
no mortality
essential when there are some degrees of soft tissues involvement such as in cavernous sinus thrombosis (958). Moreover, if
meningitis is suspected, a lumbar puncture could be useful (958)
once an abscess has been excluded.
High dose long term i.v. antibiotic therapy followed by craniotomy and surgical drainage are usually required for successful treatment (351). Pathogens most commonly involved in the
pathogenesis of endocranial complications are Streptococcus
and Staphylococcus species and anaerobes (973).
signs of meningeal irritation associated with spiking fevers and

prostration. (964).
The cornerstone of diagnosis is high-resolution CT scan with
orbit sequences (975) which show low enhancement compared to
normal (976). A mortality rate of 30% and a morbidity rate of 60%
remain in the adult population. No data are available for the
paediatric population in which the mortality rate for intracranial complications is 10% to 20% (977). The use of anticoagulants
in these patients is still controversial (964) but is probably indicated if imaging shows no evidence of any intracerebral haemorrhagic changes (978).
8-5 Cavernous sinus thrombosis

When the veins surrounding the paranasal sinuses are affected,
further spread can lead to cavernous sinus thrombophebitis
causing sepsis and multiple cranial nerve involvement (967). Such
a complication has been estimated at 9% of intracranial complications (958, 974) and is a fortunately rare and dramatic complication of ethmoidal or sphenoidal sinusitis. (968).
The main symptoms are bilateral lid drop, exophthalmos, ophthalmic nerve neuralgia, retro-ocular headache with deep pain
behind the orbit, complete ophthalmoplegia, papilloedema and
8-6 Osseous complications

Sinus infection can also extend to the bone producing
osteomyelitis and eventually involving the brain and nervous
system. Even if the most frequent intracranial spread is due to
frontal sinusitis, any sinus infection can lead to such a complication (964). The most common osseous complications are osteomyelitis of the maxillary (typically in infancy) or frontal bones (976).
As vascular necrosis results from frontal sinus osteitis, an
osteomyelitis of the anterior or posterior table of the frontal
83
sinus is evident. On the anterior wall it presents clinically with

doughy oedema of the skin over the frontal bone producing
a mass (Potts puffy tumor) whereas from the posterior wall
spread occurs directly or via thrombophlebitis of the valveless
diploic veins leading to meningitis, peridural abscess or brain
abscess (964).
Ocular signs can appear controlaterally. Contrast-enhanced CT

scan confirms the diagnosis. A lumbar puncture, though contraindicated if intracranial pressure is elevated, can also be useful.
Therapy includes a combination of i.v. broad-spectrum antibiotics administration and surgical debridement of sequestered
bone and drainage (964).
In this context, Gallagher (958) reviewing the files of 125 patients

with complicated rhinosinusitis, found that osteomyelitis
developed in about 9% of cases. The sinus walls were affected
in 32% of patients in Ogunleyes data (955). Lang in 2001 recorded 10 cases of subdural empyema in adults and children secondary to frontal sinus infection: among them 4 had Potts
puffy tumor and 1 had periorbital abscess (948).
8-7 Unusual complications of rhinosinusitis
Signs and symptoms of intracranial involvement are soft tissue

oedema (especially of the superior lid), high fever, severe
headache, meningeal irritation, nausea and vomiting, diplopia,
photophobia, papilloedema, coma and focal neurological signs.
Table 8-3. Unusual complications of rhinosinusitis

complication
author, year
lacrimal gland abscess
Mirza 2001 (949)

Patel 2003 (950)
nasal septal perforation
Sibbery 1997 (979)
visual field loss
Gouws 2003 (952)
mucocoele or mucopyocoele
Low 1997 (972)
displacement of the globe
Low 1997 (972)
septicaemia
Rimal 2006 (1110)
84
Supplement 20
9. Special considerations: Rhinosinusitis in children special

9-1 Introduction
Rhinosinusitis is a common problem in children that is often
overlooked. It is a multifactorial disease in which the importance of several predisposing factors changes with age and is
different from the adult form of the disease in many respects
(Table 1). The management of rhinosinusitis in children is a
controversial and rapidly evolving issue.
present, but they gradually develop from the anterior ethmoid

cells into the cranium. When the upper edge of the aircell
(cupola) reaches the same level as the roof of the orbit, it can
be termed a frontal sinus, a situation that appears around the
age of five. When a child reaches the age of 7-8 years the floor
of the maxillary sinus already occupies the same level as the
nasal floor.
9-3 Epidemiology and pathophysiology
Table 9-1. Differences between paediatric and adult chronic rhinosinusitis

young children
adults
Coagulase negative
staphylococci
30%
35%
Staphylococcus aureus
20%
8%
Haemophilus influenzae
40%
0%
Moraxella catarrhalis
24%
0%
Commensal microflora
Streptococcus pneumoniae
50%
26%
Corynebacterium species
52%
23%
Streptococcus viridans
30%
4%
Immunity
immature:
defective response
to polysaccharide
antigens
(IgG2, IgA)
mature, except
in a subset
History
self-limited in
time (improves
after the age of 6-8
years)
no history of
spontaneous
improvement
after certain age
Histology
mainly neutrophilic disease, less

basement membrane thickening
and mucus gland
hyperplasia, more
mast cells (Sobo
2003)
mainly
eosinophils
Endoscopy
polyps are rare,

except in CF
polyps frequently
present
CT-scan
younger child
more diffuse
sinusitis, involving
all sinus
sphenoid and
posterior sinus
less often
involved
9-2 Anatomy
In the newborn, the maxillary sinus extends to a depth of
about 7 mm, is 3 mm wide and 7 mm high (980). In the newborn,
two to three ethmoid cells are found bilaterally, and by the age
of four the ethmoid labyrinth has formed. The sphenoid sinuses are also present in the neonate. Each sphenoid sinus is 4
mm wide and 2 mm high. At birth the frontal sinuses are not
Since the introduction of CT-scanning, it has become clear

that a runny nose in a child is not only due to limited rhinitis
or adenoid hypertrophy, but that in the majority of the cases
the sinuses are involved as well. Van der Veken (220) in a CT
scan study showed that in children with a history of chronic
purulent rhinorrhea and nasal obstruction, 64 % showed
involvement of the sinuses. In a MRI study of a non-ENT paediatric population (981) it was shown that the overall prevalence
of sinusitis signs in children is 45 %. This prevalence increases
in the presence of a history of nasal obstruction to 50 %, to 80
% when bilateral mucosal swelling is present on rhinoscopy, to
81 % after a recent upper respiratory tract infection (URTI),
and to 100 % in the presence of purulent secretions. Also
Kristo et al (982) found a similar overall percentage (50 %) of
abnormalities on MRI in 24 school children. They included,
however, a follow-up after 6 to 7 months, and found that about
half of the abnormal sinuses on MRI findings had resolved or
improved without any intervention.
Epidemiologic studies on rhinosinusitis in children are limited
but reveal the following information on the pathophysiology
and clinically relevant factors influencing the prevalence of rhinosinusitis in children:
1. There is a clear-cut decrease in the prevalence of rhinosinusitis after 6 to 8 years of age. This is the natural history of
the disease in children and is probably related to an immature
immune system in the younger child (222, 223)
2. In temperate climates there is a definite increase in the
occurrence of CRS in children during the autumn and in the
wintertime, so that the season seems to be another important
factor (222).
3. Younger children staying in day care centres show a dramatic increase in the prevalence of chronic or recurrent rhinosinusitis compared to children staying at home. See also section
1-1.
Although viruses are uncommonly recovered from sinus aspirates (983), most authors agree (984, 985) that viral infections are the
trigger to rhinosinusitis. Although CT scan abnormalites can
be seen up to several weeks after the onset of a URTI, one can
assume that only 5 to 10 % of the URTIs in early childhood are
85
complicated by ARS (986). The time course (i.e. clinical symptoms) of viral to bacterial rhinosinusitis is the same as in
adults.
meatus in 50% in one study (989).Turbinate swelling was present

in 29% in another (988). Lymphoid hyperplasia of the tonsils,
adenoids and parapharyngeal wall may also be observed. The
cervical lymph nodes may be moderately enlarged and slightly
tender (992, 994).
The most common bacterial species isolated from the maxillary sinuses of patients with ARS are Streptococcus pneumoniae,
Haemophilus influenzae, and Moraxella catarrhalis, the latter
being more common in children (45, 46).
9-4 Symptoms and signs
Anterior rhinoscopy remains the first step but is inadequate by

itself.
Endoscopy with a 2.7 mm rigid endoscope in the younger child
(when possible a 4 mm in the older child) is more useful then
flexible nasendoscopy, not only for the diagnosis but also for
the exclusion of other conditions such as: presence of polyps,
foreign bodies, tumours and septal deviations. In the younger
child total anaesthesia is necessary to perform a thorough nasal
endoscopy. Moreover it allows direct sampling of middle meatus flora.
Table 9-2. Presenting symptoms of rhinosinusitis in children. (223, 988, 989).
9-6 Investigations
Antral punctures are now rarely performed in children but it is

interesting to know from studies in the past there is a good correlation of bacteriology between the maxillary sinus and the
middle meatal specimen (83 %), and a poor correlation between
those of the nasopharynx and the maxillary sinus (45 %) (987).
rhinorrhoea (71 to 80 %)
all forms
cough (50 to 80 %)
all forms
fever (50 to 60 %)
acute
pain (29 to 33 %)
acute
nasal obstruction (70 to 100 %)
chronic
mouth breathing (70 to 100 %)
chronic
ear complaints (recurrent purulent

otitis media or OME in 40 to 68 %)
chronic
Wald stresses that 3 common clinical developments should

alert a clinician to the possibility of rhinosinusitis (990):
1. signs and symptoms of a cold that are persisting beyond 10
days (any nasal discharge, daytime cough worsening at night)
2. a cold that seems more severe then usual (high fever, copious purulent discharge, peri-orbital oedema and pain)
3. a cold that after several days of improvement worsen (with
or without fever) .
The neutrophil content of nasal brushings if >or=5% predicts
maxillary sinusitis as judged from X rays with a sensitivity of
91% and a predictive value of 84%, but only in non-allergic
children (991).
9-5 Clinical examination
Physical examination of a child's nose is often difficult, and
only limited rhinoscopy is tolerated. The examination may be
simply accomplished by lifting the tip of the nose upwards
(young children have wide noses with round nostrils, allowing
easy examination of the condition of the inferior turbinates).
Another convenient method is the use of an otoscope (992,
993)
.Usually the nasal and pharyngeal mucosa appears erythematous with yellow to greenish purulent rhinorrhoea of varying
viscosity. A post nasal drip was seen in 60%, pus in the middle
9-6-1 Microbiology
Microbiological assessment is usually not necessary in children
with uncomplicated acute or chronic rhinosinusitis.
Indication for microbiology are: (995)
1. severe illness or toxic child;
2. acute illness in a child not improving with medical therapy
within 48-72 hours;
3. an immuocompromised host;
4. the presence of suppurative (intra-orbital, intracranial)
complications (orbital cellulitis excepted).
Quantification of bacterial growth can also help in distinguishing contamination from real infection, and isolates should be
considered positive when a type of bacteria is present in a
quantity of at least 10,000 colonies/ml (990).
9-6-2 Imaging
Imaging is not necessary to confirm the diagnosis of rhinosinusitis in children. The increase in thickness of both the soft
tissue and the bony vault of the palate in children under 10
years of age limits the usefulness of transillumination and
ultrasonography in the younger age group (505).
Plain X-rays are insensitive with limited usefulness for diagnosis or to guide surgery and correlate very poorly with CT scans.
The marginal benefits are insufficient to justify the exposure to
radiation (220).
CT scanning remains the imaging methodology of choice,
because of its ability to resolve both bone and soft tissue, with
good visualisation of the ostiomeatal complex. The indications
for CT scanning in a child are the same as those given previously for a microbiology specimen with one extra indication
which is if surgery is being considered after failure of medical
therapy. The high incidence of asymptomatic children with CT
scan abnormalities (996) must be remembered plus the fact that
such children do not require treatment. (997).
86
A number of studies suggest that the growth of the maxillary

sinus is not impaired by extensive or chronic disease, unlike
the temporal bone and it seems that the presence of a
hypoplastic maxillary sinus per se is not an indication for
surgery (998)
9-6-3 Additional investigations
In the presence of recalcitrant rhinosinusitis, underlying conditions must be considered, preferably before undertaking any
surgical procedure.
9-6-3-1 Allergy
The role of atopy in chronic rhinosinusitis is unclear. Many
authors attribute a great deal of importance to allergy (101, 988, 993)
although others (61, 220, 999) did not find an increased prevalence of
rhinosinusitis in allergic children.
In a CT scan study Iwens et al. (1994) found signs of mucosal
inflammation in 61 % of atopic children (61). Ramadan (1999)
showed that allergic patients had a higher CT scan score than
non-allergic patients (875). Allergic children have more URT
problems and more time off school than their non-allergic
peers (1000). Therefore in children with CRS and with a suggestive history (asthma, eczema), and/or physical examination
findings (allergic salute, watery rhinorrhea, nasal blockage,
sneezing, boggy turbinate), allergic assessment (skin prick,
RAST) should be performed.
9-6-3-2 Immune deficiency
All young children have a physiologic primary immune deficiency (993, 1001). Defence against polysaccharide encapsulated bacteria
via immunoglobulin G subclasses 2 and 4 may not reach adult
levels until the age of 10 years (1002). IgG subclass deficiency can
lead to protracted or chronic rhinosinusitis (1003-1005). According to
Polmar (1004) recurrent and chronic rhinosinusitis is the most
common clinical presentation of common variable immunodeficiencies. Although not all patients who lack secretory IgA antibodies have an increased number of more severe respiratory
infections, the subject who has IgA deficiency and chronic rhinosinusitis is a difficult management problem, especially if an
IgG subclass deficiency is also present. Replacement therapy
cannot be provided (1005). Patients with primary or acquired
immune deficiencies (e.g. treatment for malignancies, organ
transplants, maternally transmitted AIDS or blood-transmitted
AIDS in haemophilics, drug induced conditions) are at risk for
developing a difficult-to-treat rhinosinusitis with resistant or
uncommon micro-organisms and fungi. Also the initial signs
and symptoms may be non-specific, such as thin rhinorrhea,
mild congestion, and chronic cough (993).
9-6-3-3 Cystic fibrosis
Cystic fibrosis is caused by a mutation of the gene FES1
encoding the cystic fibrosis transmembrane conductance regulator (CFTR). This gene contains 27 exons encompassing
approximately 252 kb of DNA on chromosone 7q 31.2. The
Supplement 20
most common mutation, deletion of phenylalanine at position

508 (F508) accounts for nearly 70 % of mutuations in
European-derived Caucasian population (1006).
In children with cystic fibrosis, sinusitis is a common problem.
Although the prevalence of nasal disease was previously estimated to be between 6 and 20 % (1007), Yung et al (1008) found it to
be over 50 % and Brihaye et al. (1009) reported that performing
rigid endoscopy in 84 patients with cystic fibrosis, revealed
inflammatory polyps in 45 % (mean age 15 years) and medial
bulging of the lateral nasal wall in 12 % (mean age 5 years). In
patients with cystic fibrosis and chronic rhinosinusitis, CT
showed in 100 % (1009) opacification of the anterior complex
(anterior ethmoid, maxillary and -if developed- frontal sinus)
and 57 % showed clouding of the posterior complex (posterior
ethmoid and sphenoid). In all children with a medial displacement of the lateral nasal wall, there was a soft tissue mass in the
maxillary antrum (large quantity of secretions surrounded by
polyposal mucosa, representing a mucopurulent rhinosinusitus). In 80 % of these children the displacement was so extreme
that the lateral nasal wall touched the septum, resulting in total
nasal blockage. In a study by Brihaye et al (1009) massive polyposis
was never found before the age of 5 years. Mucopurulence in
the maxillary sinus occurs at a younger age (3 months to 8
years) and the maxillary sinus seems to be the first sinus affected by the disease. Recent data suggest that CF heterozygotes
are over-represented in the paediatric CRS population (1010).
9-6-3-4 Primary ciliary dyslcinesia
Primary ciliary dyskinesia (PCD) (1011), an autosomal recessive disorder involving dysfunction of cilia is present in 1 of 15000 of the
population and should always be considered in any neonate with
respiratory or ENT problems of unknown origin. At least half of
the PCD patients have symptoms when first born and especially
in a term baby with no risk factor for congenital infection showing signs of rhinitis at birth, PCD should be excluded. The same
applies to an infant or older child with atypical asthma, unresponsive to treatment, chronic wet cough and sputum production, very severe gastro-oesophageal reflux, bronchiectasis, rhinosinusitis (rarely with polyposis), chronic and severe secretory
otitis media, particularly with continuous, long lasting and diffuse
discharge from the ears after grommet insertion. Roughly half
the children with PCD have situs inversus and bronchiectasis in
addition to rhinosinusitis ( Kartageners syndrome).
There are two ways to screen for PCD: saccharine test and
nasal nitric oxide. The saccharine test is a cheap and easy procedure to screen older children and adults, but is relatively
unreliable Nasal nitric oxide (nNO) measurements can be
made in children over 5years old. Recent data suggests that
PCD epithelia have a common defect a lack of inducible
nitric oxide synthase. In PCD values of nNO are usually less
than 100; values exceeding 250ppb have a sensitivity of 95 %
for excluding the diagnosis of PCD (1012). Since very low nNO
87
values can occur with severe nasal congestion the procedure

should be repeated after decongestion or a brief course of oral
plus topical corticosteroids.
If the child is too young for the tests, if there is any doubt
about the validity of the saccharine test, or the results are positive (transport time longer than 60 minutes, nNO less than
250ppb) or there exists a strong clinical suspicion, the ciliary
beat frequency should be tested from a nasal epithelial biopsy.
discharge concluded that antibiotics given for 10 days reduced

the probability of persistence in the short to medium term.
The benefits were modest and for 8 children treated one additional child would be cured ( NNT 8, 95% CI 5 to 29). No long
term benefits were documented. This meta-analysis is a combination of studies in rhinosinusitis in children with symptoms
for as little as 10 days (1017) to more than 3 months (1018). Two
more recent RCT comparing antibiotics to placebo or another
therapy do not alter the conclusions of the meta analysis (1019,
1020)
. According to the members of the consensus meeting in
Brussels, 1996: Management of rhinosinusitis in children: (1021)
antibiotics should be reserved largely for severe disease e.g.:
1. a severe illness or toxic condition in a child with suspected
or proven suppurative complication. Intravenous administration of an appropriate agent is recommended. The
antibiotic selected should be effective against the penicillin-resistant Streptococcus pneumonia, beta-lactamase
producing H. influenzae and Moraxella catarrhalis
2. severe acute rhinosinusitis: in ambulatory patients for
whom oral therapy is appropriate, an agent should be
selected that is resistant to the action of beta-lactamase
enzymes (amoxicillin-potassium clavunate or a second generation cephalosporin such as cefuroxime axetil)
3. non-severe acute rhinosinusitis: only in a child with protracted symptoms to whom antibiotics can be given on an
individual basis (presence of asthma, chronic bronchitis,
acute otitis media etc.)
If direct inspection of the ciliary beat frequency is abnormal

(less than 11-16 Hz) an ultrastructure study of cilia is needed.
The most common ciliary abnormalities in PCD are: dynein
arm defects (absence or reduced number of inner, outer or
both dynein arms), tubular defects (transposition and extra
microtubules), radial spokes defects or absence, ciliary dysorientation (suspected if mean standard deviation of angle is larger than 20), abnormal basal apparatus, ciliary aplasia, abnormally long cilia (1013). Many of these abnormalities on TEM
(transmission electron microscopy), however, can be transient
or occur secondarily after infection. Secondary ciliary dyskinesia, the acquired form (infections, inflammatory or toxic) is
mostly correlated with other anomalies, such as microtubular
abnormalities and composed cilia. However, there exists a
great overlap of ultrastructural abnormalities between the two
(534)
. Therefore the study of cilia after sequential monolayer-suspension culture technique excludes the acquired form (1014).
9-6-3-5 Gastro-oesophageal reflux
The parallel existence of upper airway inflammation with ensuing problems of intractable rhinosinusitis, otitis, and gastrooesophageal reflux (GER) has been observed and suggests a
causal relationship. Barbero found in a group of patients with
upper airway disease and GER, that anti-reflux measures may
permit a greater well-being and that GER maybe among the
variables leading to refractory chronic upper airway disease (1015).
The otolaryngologist should be suspicious of GER in children
complaining of chronic nasal discharge and obstruction combined with chronic cough, hoarseness and stridulous respiration. The endoscopic appearance of the laryngeal and tracheal
areas are of considerable importance in conjunction with
oesophageal examination, in determining the potential relationship between GER and otolaryngologic abnormalities. The
diagnosis needs to be confirmed by oesophageal 24 hours pH
monitoring: in 30 children with chronic sinus disease 63 % had
oesophageal reflux and 32 % had nasopharyngeal reflux (772).
9-7 Management
9-7-1 Management of acute rhinosinusitis in children
Just as in adults acute rhinosinusitis in children usually only
needs symptomatic treatment.
9-7-1-1 Antibiotics in ARS in children
A Cochrane meta-analysis (1016) of antibiotics for persistent nasal
In those children for whom antibiotic therapy is preferred,

amoxycillin (45 mg/kg/day, doubled if under 2 or with risk factors for resistance) is appropriate. If the patient's condition has
not improved within 72 hours, a change of antibiotic to an
agent effective against the resistant organism prevalent in the
community should be considered.
Patients with a penicillin allergy should receive a suitable alternative antibiotic such as azithromycin or clarithromycin as
first-line therapy.
9-7-1-2 Topical corticosteroids in ARS
Topical corticosteroids may be a useful ancillary treatment to
antibiotics in childhood rhinosinusitis, effective in reducing the
cough and nasal discharge earlier in the course of ARS (610 , 1022).
There are a large number of studies showing that local corticosteroids are effective and safe in children with rhinitis (1023-1027).
9-7-1-3 Topical or oral decongestants
Most authors prefer topical 2 agonists (xylo- and oxymetazoline) in appropriate concentrations. Careful dosage is important when treating infants and young children, to prevent toxic
manifestations.
A double blind, randomised controlled trial (RCT) by Michel (1028)
(III, no power), compared isotonic EMS solution (balneotherapeutic water) with xylometazoline 0.05% solution in the treat-
88
ment of acute rhinosinusitis with middle ear involvement during

14 days in 66 children, aged 2-6 years, and revealed no difference
in improvement in both groups, in terms of mucosal inflammation, nasal patency, middle ear function and general state of
health, as outcome measures (1028). A double blind, randomised
controlled trial (RCT) by McCormick (707) showed no additive
effect of adding decongestant-antihistamine (nasal oxymetazolone and oral syrup containing brompheniramine and phenylpropanolamine) to amoxicillin (III, no power).
9-7-1-4 Nasal douching
Saline nose drops or sprays are popular with paediatricians (993,
994, 1005)
. As long as the saline is isotonic and at body temperature, it can help in eliminating nasal secretions and it can
decrease nasal oedema.
9-7-2 Management of chronic rhinosinusitis in children
Chronic rhinosinusitis in the young child does not have to be
treated, as spontaneous resolution is the norm (1029). Van Buchem
et al. followed 169 children with a runny nose for 6 months,
treating them only with decongestants or saline nose drops.
They did not find a single child who developed a clinically serious disease with general symptoms such as marked pain, pressure on sinuses, local swelling, or empyema, showing that complications of rhinosinusitis in a child are uncommon (223).
9-7-2-1 Treatment of chronic rhinosinusitis
The data on specific treatment of CRS in children very are limited. A quality of life tool for children SN-5 is now available (584).
9-7-2-2 Antibiotics
As described under 9-7-1-1 Antibiotic in ARS in children a
Cochrane meta-analysis (1016) of antibiotics for persistent nasal
discharge concluded that antibiotics given for 10 days reduced
the probability of persistence in the short to medium term.
The benefits were modest and for 8 children treated one additional child would be cured ( NNT 8, 95% CI 5 to 29). No long
term benefits were documented. The only study really treating
CRS (1018) was negative.
9-7-2-3 Topical corticosteroids
There are no data describing the efficacy of topical corticosteroids in paediatric CRS. There are a large number of studies
showing that local corticosteroids are effective and safe in children with rhinitis (1023-1027) and one may assume that the same is
true for CRS (level IV).
9-7-2-4 Nasal douching
In one double-blind RCT twenty children aged 3 to 14 years
with a history of bronchial asthma complicated by chronic
sinusitis were studied in a double-blind study. Patients
received, at random, over a period of 2 weeks, either 2 ml
saline or 2 ml bromhexine (2 mg/ml) t.i.d. by means of a home
nebulizer. Both types of nebulization were equally efficient in
Supplement 20
reducing the symptom score (level III, no power) (717). A second

randomized study in thirty children with CRS aged 3 to 16
years compared the effect of 4 weeks of douching with hypertonic saline (HS) (3.5%) versus normal saline (NS) (0.9%). Both
treatments were effective although the HS seemed to be a little
more effective than the NS (751). No data on side effects were
given (level III).
9-7-2-5 GER therapy
In children with chronic rhinosinusitis and gastro-oesophageal
reflux (GER) proven by 24 hours of pH monitoring Phipps et al.
(772)
found that most children showed improvement of sinus disease. Bothwell et al. (1030) suggested that in 89 % of the children (25
out of 28) surgery could be avoided. These studies indicate that
GER should be evaluated and treated in children with chronic
sinus disease before sinus surgical intervention (level III).
9-7-2-6 Effect on asthma
In a study of eighteen children with sinusitis and asthma, medical treatment of sinusitis with topical corticosteroids, antibiotics and 2 days of oral steroid improved asthma and increased
the interferon gamma/ IL4 ratio in nasal lavage (1031). Tsao
noted that nasal douching improved bronchial hyperreactivity
in asthmatic children (1032) level III.
9-7-2-7 Surgical treatment of rhinosinusitis
In chronic rhinosinusitis surgery should follow thorough investigation of underlying factors and a prolonged trial of medical
therapy.
The following procedures are ineffective and therefore not recommended: antral lavage (992, 1033), inferior meatal antrostomy (992,
1034)
, except possibly in PCD. The Caldwell Luc operation is
contra-indicated because it can damage unerupted teeth (993, 1005).
Most of the controversies seem to centre on the indications for
functional endoscopic sinus surgery in children. (FESS or paediatric FESS=PESS). The "functional" in FESS stands for the
restoration of the function of the ostiomeatal complex i.e. ventilation and drainage. In 1998 an international consensus was
reached concerning the indications of FESS in children (1021):
a. absolute indications:
1. complete nasal obstruction in cystic fibrosis due to massive polyposis or due to medialization of the lateral
nasal wall;
2. orbital abscess;
3. intracranial complications;
4. antrochoanal polyp;
5. mucocoeles or mucopyocoeles;
6. fungal rhinosinusitis;
b. possible indications:
in chronic rhinosinusitis with frequent exacerbations that
persist despite optimal medical management and after
exclusion of any systemic disease, endoscopic sinus surgery
89
is a reasonable alternative to continuous medical treatment. Optimal management includes a 2-6 weeks of adequate antibiotics (IV or oral) with treatment of concomitant disease.
required, complication rates are around 11% in a recent study

(886)
. The results are less good than in non-CF children with
around 50% of children reporting improvement at 2 years.
However, sinus surgery post-lung transplantation is associated
with a lower incidence of tracheobronchitis and pneumonia (888).
Surgery for chronic rhinosinusitis with frequent exacerbation is

mostly limited to a partial ethmoidectomy: removal of the
uncinate process, with or without a maxillary antrostomy in
the middle meatus, and opening of the bulla is often sufficient.
In other cases such as in cystic fibrosis with massive polyposis,
extensive ethmosphenoidectomy may be necessary.
Most results are judged on symptomatic relief and do not
include endoscopic examination or CT scan.
A meta-analysis performed by Hebert et al. (1035) showed in 8
published articles (832 patients) positive outcome rates going
from 88 to 92 %. The average combined follow-up was 3.7
years. They concluded that FESS is a safe and effective treatment for chronic rhinosinusitis that is refractory to medical
treatment. Further, similar results have been published (1036-1038).
Lieu and Piccirrillo (1039) retrospectively analysed the results of
ESS in 133 children unresponsive to medical therapy using a 4
stage classification and suggested that operation was particularly effective for those in the intermediate stages.
Chan (1999) reported on 14 children with post FESS refractory
rhinosinusitis and noted that 10 of them who were operated
when under 4.8 years needed a disproportionately higher rate
of further surgical intervention compared to the remaining
clinical population. Ostiomeatal scarring was the most difficult
complication (1040). They recommended judicious use of FESS
in the very young. ESS is unlikely to be successful in under
three year olds (1041) and its efficacy is reduced if the child is
exposed to tobacco smoke. (1042). Disease duration prior to
surgery does not affect outcome (1043). Intravenous dexamethasone per-operatively reduced swelling and scarring and was
particularly useful in children with asthma, lower CT grades,
no tobacco smoke exposure and in those over 6 years (1044).
Similar results were published by Jiang et al. (1036) and Fakhri et
al. (1037) showing a postoperative improvement in 84 % of the
FESS patients (n=121). For this indication Bothwell et al. (1038)
found no statistically significant difference in the outcome of
facial growth between a retrospective age-matched cohort outcome study between 46 children who underwent FESS surgery
and 21 children who did not, using qualitative antropomorphic
analysis of 12 standard facial measurements after a 13.2 years
follow-up.
Duplechain (1045) reported for the first time the results of this
kind of surgery in cystic fibrosis children followed by many
other authors (891, 1008, 1046, 1047). Co-ordinated care by paediatricians,
pulmonologists anaesthetists, surgeons and physiotherapists is
The effectiveness of adenoidectomy in the management of

paediatric rhinosinusitis is still a controversial issue. It is difficult to differentiate between the symptoms typical for chronic
rhinosinusitis and those of adenoid hypertrophy. Hibert (1048)
showed that nasal obstruction, snoring and speech defects
occur more frequently in children with adenoid hypertrophy
while symptoms of rhinorrhoea, cough, headache, signs of
mouth breathing, and abnormalities on anterior rhinoscopy
occur as frequently in children with chronic rhinosinusitis as in
children with adenoid hypertrophy.
Antibiotic-resistant bacteria were found on adenoid tissue culture in 56% of children undergoing adenoidectomy for hypertrophy plus OME and CRS compared to 22% undergoing adenoidectomy for hypertrophy without those complications (1049).
Wang et al. e.g. found no significant correlation between the
size of the adenoid and the presence of purulent secretions in
the middle meatus on fibreoptic examination in 420 children
between the age of 1 and 7 years, while there was a very significant correlation between the size of the adenoid and the complaints of mouth breathing (p<0.001) and snoring (p<0.001)
(1050)
. The size of the adenoid and associated diseases seem to be
factors for consideration.
Adenoidectomy was included in the stepwise protocol for the
treatment of paediatric rhinosinusitis proposed by Don et al.
(1051)
. Recently Ungkanont et al. proved adenoidectomy to be
effective in the management of paediatric rhinosinusitis. They
suggest performing an adenoidectomy as a surgical option
before endoscopic sinus surgery (ESS), especially in younger
children with obstructive symptoms (1052).
Ramadan (1999) has undertaken a prospective non- randomized study comparing ESS to adenoidectomy in the treatment
of rhinosinusitis in 66 children with improvement in 77% 0f
31 children in the ESS group compared to 47% of 30 in the
adenoidectomy group., (OR 3.9, p=0.01) (1053). Multivariate
analysis demonstrated that ESS was significantly better after
age, sex, allergy, asthma, day care and CT stage were adjusted
for (OR 5.2,p=0.03). Asthma was an independent predictor of
success (OR 4.3, p=0.03).
90
Supplement 20
10. Chronic rhinosinusitis with or without nasal polyps in

relation to the lower airways
10-1 Introduction
Due to its strategic position at the entry of the airway, the nose
plays a crucial role in airway homeostasis. By warming up,
humidifying and filtering incoming air, the nose is essential in
the protection and homeostasis of lower airways (1054) The nose
and bronchi are linked anatomically, are both lined with a
pseudo-stratified respiratory epithelium and equipped with an
arsenal of innate and acquired immune defense mechanisms.
It is not hard to imagine that nasal conditions causing nasal
obstruction may become a trigger for lower airway pathology
in susceptible individuals. In chronic sinus disease with nasal
polyps (1055) total blockage of nasal breathing may occur, hence
bypassing nasal functions that may be relevant in preventing
lower airway disease. It is, however, evident that the nasobronchial interaction is not restricted to bronchial repercussions of hampered nasal air conditioning. Nose and bronchi
seem to communicate via mechanisms such as neural reflexes
and systemic pathways. Bronchoconstriction following exposure of the nose to cold air suggests that neural reflexes connect nose and lung (1056). Recently, the systemic nature of the
interaction between nose and bronchi has been proposed.
Indeed, many inflammatory diseases of the upper airways
show a systemic immunologic component involving the blood
stream and bone marrow (1057). In addition, genetic factors may
also play a role in the manifestation of nasal and/or bronchial
disease (1058). In spite of the fact that aspiration of nasal contents
may take place in neurologically impaired individuals, it is not
clear whether micro-aspiration of nasal contents plays a role in
the development or severity of bronchial disease (1059).
10-2 Asthma and Chronic Rhinosinusitis without NP
Bronchial asthma is considered a comorbid condition of CRS.
In some centres, around 50% of patients with CRS have clinical asthma (1060, 1061) Interestingly, most patients with CRS who
do not report having asthma show bronchial hyperreactivity
when given a metacholine challenge test (1061). Others report
that 60 % of patients with CRS have lower airway involvement,
assessed by history, pulmonary function and histamine provocation tests (865). Alternatively, sinonasal symptoms are frequently reported in asthmatic patients, ranging up to 80 % in
some studies. Radiologic imaging of the sinuses has demonstrated mucosal thickening of the sinus mucosa in up to 84 %
of patients with severe asthma (1062). However, these epidemiologic and radiologic data should be interpreted with caution as
they may reflect a large referral bias.
CRS is currently thought to have a multifactorial etiology, in
which host factors like anatomical, local defense and immunologic factors, act in synergy with microbial and environmental
factors in the development and chronicity of the disorder.
Histopathologic features of CRS and asthma largely overlap.
Heterogeneous eosinophilic inflammation and features of airway remodeling like epithelial shedding and basement membrane thickening, are found in the mucosa of CRS and asthma
patients (1061). Cytokine patterns in sinus tissue of CRS highly
resemble those of bronchial tissue in asthma (30), explaining the
presence of eosinophils in both conditions. Therefore,
eosinophil degranulation proteins may cause damage to the
surrounding structures and induce symptoms at their location
in the airway. Finally, lavages from CRS patients show that
eosinophils were the dominant cell type in both nasal and
broncho-alveolar lavages in the subgroup of patients with CRS
with asthma (266). Beside the similarities in pathophysiology,
sinusitis has been aetiologically linked to bronchial asthma,
and vice versa. As is the case in allergic airway inflammation,
sinusitis and asthma can affect and amplify each other via the
systemic route, involving interleukin (IL)-5 and the bone marrow. In both CRS and allergic asthma, similar pro-inflammatory markers are found in the blood. Recently, nasal application
of Staphylococcus aureus enterotoxin B has been shown to
aggravate the allergen-induced bronchial eosinophilia in a
mouse model (422). Here, mucosal contact with enterotoxin B
induced the systemic release of the typical T helper 2 cytokines
IL-4, IL-5 and IL-13, leading to aggravation of experimental
asthma. However, the interaction between both rhinosinusitis
and asthma in not always clinically present, as Ragab et al. (266)
found no correlation between rhinosinusitis and asthma severity. However, patients with asthma showed more CT scan
abnormalities than non-asthmatic patients (1063), and CT scan
abnormalities in severe asthmatic patients correlated with sputum eosinophilia and pulmonary function (1062).
Endoscopic sinus surgery (ESS) for CRS aims at alleviating
sinonasal symptoms but also improves bronchial symptoms
and reduces medication use for bronchial asthma (861, 863, 1064, 1065).
After a mean follow-up period of 6.5 years, 90% of asthmatic
patients reported their asthma was better than it had been
before the ESS, with a reduction of the number of asthma
attacks and medication use for asthma (1060). Also in children
with chronic rhinosinusitis and asthma, sinus surgery improves
the clinical course of asthma, reflected by a reduced number of
asthma hospitalizations and schooldays missed (1066). Lung function in asthma patients with CRS was reported to benefit from
ESS by some authors (853, 861), but denied by others (863, 1064, 1066). Of
note, not all studies show beneficial effects of ESS on asthma
(862)
. The reason for the inconsistency in study results between
91
studies relates to the heterogeneity and small number of

patients included in these studies, and difference in outcome
parameters studied. Interestingly, the presence of lower airway
disease may have a negative impact on the outcome after ESS.
Outcomes after ESS were significantly worse in the asthma
compared to the non-asthma group (853, 1065). Poor outcomes after
ESS have also been reported in patients with aspirin-intolerant
asthma (869, 1067, 1068). On the other hand, other authors report that
asthma does not represent a predictor of poor symptomatic
outcome after primary (855, 1069) or revision ESS (1063). In a series of
120 patients undergoing ESS, Kennedy (514) reports that asthma
did not affect the outcome after ESS when comparing patients
with equally severe sinus disease, except for the worst patients,
in which asthma did adversely affect the outcome.
clinical syndrome characterized by the triad aspirin sensitivity,

asthma and nasal polyposis and has an estimated prevalence of
1% in the general population and 10% among asthmatics (556).
Until recently, no well-conducted clinical trials have been performed showing beneficial effects of medical therapy for CRS
on bronchial asthma. Ragab et al. (864) published the first randomized prospective study of surgical compared to medical
therapy of 43 patients with CRS with/without NP and asthma.
Medical therapy consisted of a 12 weeks course of erythromycin, alkaline nasal douches and intranasal corticosteroid
preparation, followed by intranasal corticosteroid preparation
tailored to the patients' clinical course. The surgical treatment
group underwent ESS followed by a 2 week course of erythromycin, alkaline nasal douches and intranasal corticosteroid
preparation, 3 months of alkaline nasal douches and intranasal
corticosteroid, followed by intranasal corticosteroid preparation tailored to the patients' clinical course. Both medical as
well as surgical treatment regimens for CRS were associated
with subjective and objective improvements in asthma state.
Interestingly, improvement in upper airway symptoms correlated with improvement in asthma symptoms and control.
10-3 Asthma and Chronic Rhinosinusitis with NP
Seven percent of asthma patients have nasal polyp (174) and in
non-atopic asthma and late onset asthma, polyps are diagnosed
more frequently (10-15%). Aspirin-induced asthma is a distinct
Increased nasal colonization by Staphylococcus aureus and presence of specific IgE directed against Staphylococcus aureus
enterotoxins was found in NP patients (415). Interestingly, rates of
colonization and IgE presence in NP tissue were increased in
subjects with NP and co-morbid asthma or aspirin sensitivity. By
their superantigenic activity, enterotoxins may activate inflammatory cells in an antigen-non-specific way. Indeed, nasal application of Staphylococcus aureus enterotoxin B is capable of
aggravating experimental allergic asthma (422). Besides bacterial
enterotoxins, Ponikau et al. report on the potentially important
role of fungi, especially Alternaria, in the generation of chronic
sinus disease with NP (1070). By their capacity to induce eosinophil
degranulation (1071), Alternaria may contribute to the inflammatory spectrum of CRS with/without NP and asthma.
No well-conducted trials on the effects of medical therapy for
NP on asthma have been conducted so far. Therefore, welldesigned trials on nasal corticosteroids, oral antibiotics, vaccination therapy or anti-leukotriene treatment in patients with
NP and asthma are warranted. After ESS for NP in patients
with concomitant asthma, a significant improvement in lung
function and a reduction of systemic steroid use was noted,
whereas this was not the case in aspirin intolerant asthma
patients (1068). In a small series of patients with NP, endoscopic
sinus surgery did not affect the asthma state (589). However,
nasal breathing and quality of life improved in most patients.
10-4 COPD and rhinosinusitis
Up to 88 % of patients with COPD presenting at an academic
unit of respiratory disease may experience nasal symptoms,
most commonly rhinorrhoea (1072). Nasal symptoms in COPD
patients correspond well with an overall impairment of the
quality of life (1072). So far, no further information is available on
the nasobronchial interaction in COPD patients.
92
Supplement 20
11. Socio-economic cost of chronic rhinosinusitis and nasal polyps

11-1 Direct Costs
Chronic rhinosinusitis, can be debilitating for patients and
imposes a major economic cost on society in terms of both
direct costs as well as decreased productivity. To better evaluate the socioeconomic impact of chronic rhinosinusitis, the
current English literature has been reviewed. Data from outside the USA are very limited. In a 1999 publication, Ray et al
(3)
estimated the total direct (medical and surgical) costs of
sinusitis to be a staggering $5.78 billion in the US. This figure
was extrapolated from governmental surveys such as the
national health care survey and medical expenditure data. The
cost of physician visits resulting in a primary diagnosis of
sinusitis was $3.39 billion, which does not reflect the complete
cost of radiographic studies, medication, or productivity losses.
Acknowledging that other airway disorders are closely tied to
rhinosinusitis, Ray et al (3) used the Delphi method to quantify
how often rhinosinusitis is a secondary diagnosis contributing to
the primary diagnosis assigned by physicians. An expert panel
examined the co-incidence of rhinosinusitis in diseases such as
asthma, otitis media, and allergic rhinitis, and determined that
10-15% of the cost of these other diseases was attributable to rhinosinusitis, increasing the economic burden of rhinosinusitis to
the often quoted $5.78 billion sum. Rays paper relied on data
collected by the National Centre for Health Statistics and did
not attempt to distinguish ARS from the chronic form of this
disease. Addressing the cost analysis in the diagnosis of chronic
rhinosinusitis, Stankiewicz and Chow concluded that, at the present moment, subjective diagnostic paradigm for chronic rhinosinusitis is most cost-effective, although less accurate (1073).
Franzese and Stringer made an economic analysis comparing a
normal CT scan to limited coronal CT scan (1074). In this study
limited CT scan was found to be less cost-effective than the full
CT scan, costing $217,13 more per correct diagnosis
In 2002, Murphy et al (1075) examined a single health maintenance organization to evaluate the cost of CRS. The authors
compared the costs of healthcare for members with a diagnosis
of CRS to the cost of those without the diagnosis during 1994
and were able to determine the direct medical costs of the disease based on reimbursements paid rather than charges submitted. According to Murphy's study, patients with a diagnosis
of CRS made 43% more outpatient and 25% more urgent care
visits than the general population (p=0.001). CRS patients filed
43% more prescriptions, yet had fewer hospital stays than the
general HMO adult population. In total, the cost of treating
patients with CRS was $2,609 per year, 6% more than the average adult in the HMO. Because patients received all healthcare
services in one integrated system, this figure includes the costs
of radiography, hospitalization, and medication. CRS care

specifically cost $206 per patient per year, thus contributing to
a calculated nationwide direct cost of $4.3 billion annually
based on the 1994 statistic of 20.9 million individuals seeking
care for CRS. Using the more recent value of 32 million affected, (80) the overall cost would increase to $6.39 billion annually.
Addressing the cost of pharmacologic management of CRS,
Gliklich and Metson's (1076) 1998 study reported an annual
expenditure of $1220. This figure is the sum of OTC medications ($198), nasal sprays ($250), and antibiotics ($772). In an
ARS pharmacoeconomic review article on antibacterial use,
Wasserfallen et al suggest that, of the different treatment
strategies, symptomatic treatment (patients being treated with
antibacterials only if they fail to improve after 7 days) was the
most cost-effective approach, compared with treating patients
on the basis of specific clinical criteria, empirical treatment
with antibiotics, or radiology-guided treatment (1077).
Only one study in Europe has been found which considers the
costs of CRS. This study was done in patients with severe
chronic rhinosinusitis visiting a university hospital in the
Netherlands (1078). The direct cost of the CRS of these severe
patients was $ 1861/year.
No data are available distinguishing costs of nasal polyps from
CRS.
In conclusion we can deduce from these limited data that the
average direct costs of CRS per patient per year is between
$ 200,- and $ 2000,- depending on the severity of the disease.
11-2 Indirect Costs
The studies of direct medical costs demonstrate the social economic burden of the disorder. However, the total costs of CRS
are greater. With 85% of patients with CRS of working age
(between 18-65 years old) indirect costs such as missed workdays and decreased productivity at work significantly add to
the economic burden of disease(80).
Goetzel et al (2) attempted to quantify the indirect costs of rhinosinusitis. Their 2003 study resulted in rhinosinusitis being
named one of the top ten most costly health conditions to US
employers. A large multi-employer database was used to track
insurance claims through employee health insurance, absentee
days, and short-term disability claims. Episodes of illness were
linked to missed workdays and disability claims, accurately correlating absenteeism to a given disease.
In a large sample size (375,000), total healthcare payments per
93
employee per year for rhinosinusitis (acute and chronic) were

found to be $60.17, 46% of which came from the cost of absenteeism and disability. These figures approximate the cost to
employers, disregarding the cost incurred by other parties, and
therefore tremendously underestimate the entire economic
burden of the disease.
In his 2003 study, Bhattacharyya (722) used patient-completed surveys to determine the direct and indirect costs of CRS. Patients
completed a survey assessing symptoms of disease, detailing
medication use, and quantifying missed worked days attributable
to CRS. According to Bhattacharyya, the cost of treating CRS per
patient totalled $1,539 per year. Forty percent of these costs were
due to the indirect costs of missed work; the mean number of
missed workdays in this sample of 322 patients was 4.8 days (95%
CI, 3.4-6.1). Bhattacharyyas study attempts to analyze both the
direct and indirect costs of CRS and the final figures are enormous. Assuming a cost of $1500 per patient per year, and assuming CRS affects 32 million americans, the overall cost of the disease would be $47 billion if the severity of disease was similar to
that assessed in the study for all patients with the disorder.
However, this would appear to be an unlikely assumption.
It should be noted that in this last study, the patient population evaluated were generated through visits to an otorhinolaryngologist. Therefore, this patient population had already
failed initial therapy by primary care givers and possibly by
other otolaryngologists. The therapeutic interventions by the
specialist are therefore likely to be biased toward more aggressive and thus more expensive therapy.
The cost burden of absenteeism is enormous, and yet it is only
the beginning. The general health status of patients with CRS
is poor relative to the normal US population (588) . This
decreased quality of life not only leads to absenteeism, but also
contributes to the idea of presenteeism or decreased productivity when at work. Ray et al estimated by the 1994 National
Health Interview Survey, that missed worked days due to rhinosinusitis was 12.5 million and restricted activity days was
58.7 million days (3). Economic loss due to presenteeism cannot
be easily quantified, but surely increases the cost burden of the
disease.
94
Supplement 20
12. Outcomes measurements in research

Trial design has largely focussed on medical therapy. The FDA
recommends three components (1079)
1. the objective of the study must be clearly stated, coupled
with a summary of the methods used for analysis of the
results
2. the design must permit quantitative assessment of drug (ie
therapeutic) effectiveness by a valid comparison with a
control group
3. the study protocol should accurately define the design and
duration of the study, sample size issues and whether treatments are parallel or sequential.
A single primary outcome measure is preferred to minimise

the possibility of a Type I error (incorrectly assuming that a
drug is effective). However, the FDA recognises that 2 may be
appropriate.
Trials may be conducted in acute and chronic rhinosinusitis
with or without polyps and may consider single, short-term or
longer term interventions. Studies may be conducted in primary or secondary care and the criteria for diagnosis, inclusion
and exclusion together with outcome measures will depend
upon the setting.
Table 12-1 Criteria for studies conducted in primary and secondary care
criteria
primary care
secondary care
symptom profile & severity using

VAS
endoscopy (scoring eg 0-3)
imaging
plain x-ray
CT (scoring eg Lund-Mackay 0-24)
+
-
Table 12-2. Data for all studies to include:

Title
rationale for study
objectives
design
study population: inclusion & exclusion criteria
outcomes:
medication use
co-morbidity ( eg allergy, asthma,

aspirin sensitivity)
smoking history
safety assessments
additional tests (eg microbiology, smell, mediators,

cytology, mucociliary function,
haematology, airway
statistical methodology/power analysis
primary & secondary

subjective & objective
ethics approval
drop-out analysis
95
13. Evidence based schemes for diagnostic and treatment

13-1 Introduction
The following schemes for diagnosis and treatment are the
result a critical evaluation of the available evidence. The tables
Table 13-1. Treatment evidence and recommendations for adults with

give the level of evidence for studies with a positive outcome

and well powered studies with negative outcoume. Ib (-) in this
tables means a well designed (Ib) study with a negative outcome. The grade of recommendation for the available therapy
is given. Under relevance it is indicated whether the group of
authors think this treatment to be of relevance in the indicated
disease.
therapy
level
grade of
recommendation
relevance
oral antibiotic
Ia
yes: after 5 days,

or in severe cases
topical corticosteroid
Ib
yes
topical steroid and oral

antibiotic combined
Ib
yes
oral corticosteroid
Ib
yes reduces pain in

severe disease
oral antihistamine
Ib
yes, only in allergic

patients
nasal douche
Ib (-)#
no
IV
yes
Ib
yes
Table 13-2. Treatment evidence and recommendations for children

with acute rhinosinusitis
therapy
level
grade of recommendation
relevance
oral antibiotic
Ia
yes: after 5 days,

or in severe
cases
decongestant
Ib (-)#
yes, as symtomatic
relief
topical steroid on top

of oral antibiotic
mucolytics
none
no
no
topical decongestant
III (-)
no
phytotherapy
Ib
no
saline douching
IV
yes
# : Ib (-) study with a negative outcome
Table 13-3 Treatment evidence and recommendations for adults with chronic rhinosinusitis without nasal polyps *
therapy
level
relevance
oral antibiotic therapy short term < 2 weeks
Ib (-)
no
oral antibiotic therapy long term > 12 weeks
Ib (-)
yes
Antibiotics topical
III
no
steroid topical
Ib (-)
yes
steroid oral
no data
no
nasal saline douche
Ib (-)
yes
decongestant oral / topical
no data
no
mucolytics
III
no
antimycotics systemic
Ib (-)#
no
antimycotics topical
Ib (-)#
no
oral antihistamine in allergic patients
no data
no
proton pump inhibitors
no data
no
bacterial lysates
Ib (-)
no
immunomodulators
Ib (-)#
no
phytotherapy
Ib (-)#
no
anti-leukotrienes
III
no
* tSome of these studies also included patients with CRS with nasal polyps
* Acute exacerbations of CRS should be treated like acute rhinosinusitis
96
Supplement 20
Table 13-4 Treatment evidence and recommendations postoperative

care in adults with chronic rhinosinusitis without NP*
therapy
level
grade of
recommendation
relevance
oral antibiotic short

term < 2 weeks
no data
yes, immediately
postoperative,
if pus was seen
during operation
oral antibiotic
long term ~ 12 weeks
no data
yes
topical antibiotics
no data
no
topical steroid
Ib (one
+, one -)
yes
oral steroid
no data
short term yes

long term no
nasal douche
no data
available
yes
Table 13-7 Treatment evidence and recommendations for children

with chronic rhinosinusitis
Therapy
level
relevance
oral antibiotic
Ia
yes, small effect
IV
yes
saline douching
III
yes
Therapy for gastrooesophageal reflux
III
yes
* Some of these studies also included patients with CRS with nasal polyps
Table 13-5. Treatment evidence and recommendations for adults with chronic rhinosinusitis with nasal polyps *
therapy
level
relevance
oral antibiotics short term < 2 weeks
no data
no
oral antibiotic long term > 12 weeks
Ib
yes, for late relapse
topical antibiotics
no data
no
topical steroids
Ib
yes
oral steroids
Ib
yes
nasal douche
Ib no data in single use
yes for symptomatic relief
decongestant topical / oral
no data in single use
no
mucolytics
no data
no
antimycotics systemic
Ib (-)#
no
antimycotics topical
Ib (-)#
no
oral antihistamine in allergic patients
Ib (1)#
no, in allergy
capsaicin
II
no
proton pump inhibitors
II
no
immunomodulators
no data
no
phytotherapy
no data
no
anti leukotrienes
III
no
* Some of these studies also included patients with CRS without nasal polyps
Table 13-6. Treatment evidence and recommendations postoperative treatment in adults with chronic rhinosinusitis with nasal polyps*
Therapy
Level
Grade of recommendation
Relevance
oral antibiotics
short term < 2 weeks
no data
immediately post-operative,
if pus was seen during operation
oral antibiotics
long term > 12 weeks
Ib
yes
topical steroids after FESS
Ib (2 studies one + one -)
yes
topical steroids after polypectomy
Ib
yes
oral steroids
no data
yes
nasal douche
no data
yes
* Some of these studies also included patients with CRS without nasal polyps .
T
13-2 Introduction
Since the preparation of the first EP3OS document an increasing amount of evidence on the pathophysiology, diagnosis and
treatment has been published (figure1-1).
However, in compiling the tables on the various forms of therapy, it may be that despite well powered level Ib trials, no significant benefit has been demonstrated. Equally results may be
equivocal or apparently positive results are undermined by the
small number of trials conducted and/or the small number of
participants in the trial(s). In these cases, after detailed discussion, the EPOS group decided in most cases, that there was no
evidence at present to recommend use of the treatment in
question. Alternatively for some treatments no trials have been
conducted, even though the treatment is commonly used in
which case a pragmatic approach has been adopted in the recommendations.
97
98
13-3 Evidence based management scheme for adults with acute

rhinosinusitis
13-3-1 Evidence based management scheme for adults with acute
rhinosinusitis for primary care
Diagnosis
Symptom based, no need for radiology.
Supplement 20
Treatment
Treatment evidence and recommendations for acute rhinosinusitis
see Table 13-1.
Initial treatment depending on the severity of the disease:
See figure 13-1.
mild: start with symptomatic relief (decongestants, saline,
analgesics);
moderate: additional topical steroids
severe: additional antbibiotics and topical steroids
Not recommended: plain x-ray.

Symptoms
sudden onset of two or more symptoms one of which should
reduction/loss of smell;
Figure 13-1. Treatment scheme for primary care for adults with acute rhinosinusitis
99
13-3-2 Evidence based management scheme for adults with acute

rhinosinusitis for ENT specialists
Diagnosis
Symptoms
Signs
nasal examination (swelling, redness, pus);
oral examination: posterior discharge;
exclude dental infection.
ENT-examination including nasal endoscopy.
CT-Scan is also not recommended unless additional problems
such as:
very severe diseases,
immunocompromised patients;
signs of complications.
Figure 13-2. Treatment scheme for ENT specialists for adults with acute rhinosinusitis
100
13-4 Evidence based management scheme for adults with chronic

rhinosinusitis without nasal polyps
13-4-1 Evidence based management scheme for adults with CRS
with or without NP for primary care and non-ENT specialists
Diagnosis
Supplement 20
Additional diagnostic information

questions on allergy should be added and, if positive, allergy testing should be performed.
Not recommended: plain x-ray or CT-scan
Acute exacerbations of CRS should be treated like acute rhinosinusitis (1080).
Symptoms present longer than 12 weeks

two or more symptoms one of which should be either nasal
blockage/obstruction/congestion or nasal discharge
(anterior/posterior nasal drip):
Figure 13-3 Treatment scheme for Chronic Rhinosinusitis with or without nasal polyps for primary care and non-ENT specialists
101
13-4-2 Scheme for adults with CRS without NP for ENTSpecialists
Signs
ENT examination, endoscopy;
review primary care physicians diagnosis and treatment;
questionnaire for allergy and if positive, allergy testing if it
has not already been done.
Diagnosis
Two or more symptoms one of which should be either nasal
Treatment should be based on severity of symptoms

Decide on severity of symptomatology using VAS
Figure 13-4. Treatment scheme for ENT-Specialists for adults with CRS without nasal polyps
102
13-4-3 Scheme for adults with NP for ENT-Specialists

Diagnosis
Two or more symptoms one of which should be either nasal
Supplement 20
Signs
ENT examination, endoscopy;
review primary care physicians diagnosis and treatment;
questionnaire for allergy and if positive, allergy testing if
not already done.
Severity of the symptoms
(following the VAS score for the total severity) mild/moderate/severe.
Figure 13-5. Treatment scheme for ENT-Specialists for adults with CRS with nasal polyps
103
13-5 Evidence based schemes for therapy in children

The following scheme should help different disciplines in the
treatment of rhinosinusitis in children. The recommendations
are based on the available evidence, but the choices need to be
made depending on the circumstances of the individual case.
13-5-1 Evidence based management scheme for children with
Diagnosis
Symptoms
Signs (if applicable)

ENT-examination including nasal endoscopy .
such as:
very severe diseases,
Treatment
Treatment evidence and recommendations for acute rhinosinusitis
see Table 13-2.
Initial treatment depending on the severity of the disease:
See figure 13-6.
Sudden onset of two or more symptoms one of which should be either

nasal blockage/obstruction/congestion or
nasal discharge: anterior/post nasal drip;
examination: anterior rhinoscopy
X-ray/CT not recommended
Symptoms persistent
or increasing after 5 days
Symptoms less than 5 days

or improving thereafter
Common cold
Moderate
Symptomatic relief
Asthma
chronic bronchitis
No
Severe*
Non-toxic
Toxic, severely ill
Oral antibiotics
Hospitalisation
IV antibiotics
Hospitalisation
Nasal endoscopy
Culture
Imaging
IV antibiotics
and/or surgery
Yes
No effect in 48 h
Symptomatic relief
At any point
Immediate referral/hospitalisation
Periorbital oedema
Displaced globe
Double vision
Ophthalmoplegia
Reduced visual acuity
Severe unilateral or
bilateral frontal headache
Frontal swelling
Signs of meningitis or
focal neurologic signs
Oral amoxicillin
can be considered
Hospitalisation
Figure 13-6. Treatment scheme for children with acute rhinosinusitis
*
fever > 38C
severe pain
104
13-5-2 Evidence based management scheme for children with

chronic rhinosinusitis
Diagnosis
two or more symptoms one of which should be either nasal
Additional diagnostic information
questions on allergy should be added and, if positive, allergy testing should be performed.
other predisposing fsctors should be considered: immune
deficiency ( innate , acquired, GERD)
Figure 13-7 Treatment scheme for Chronic Rhinosinusitis in children
Supplement 20
Signs (if applicable)

ENT-examination including nasal endoscopy.
such as:
very severe diseases;
ENT examination, endoscopy if available.
Treatment should be based on severity of symptoms
105
14. Research needs and priorities

While our understanding of CRS has increased considerably, this
only serves to outline areas that will require further exploration
and clinical trials for validation of observations and hypotheses.
14-1 Epidemiology: Identifying the risk factors for development of
CRS and NP
Our understanding of factors predisposing to CRS and NP
remain embryonic with few studies to date. Epidemiologic studies aimed at identification of personal risk factors and environmental modifiers are required to increase our understanding of
the disease process, select appropriate populations for clinical trials and interpret information from genetic studies.
Addressing this need will require detailed assessment and longterm follow up of a well-characterised patient populations to
identify risk factors associated with development of CRS. A
prospective population study of age- and sex-matched controlled
atopic and non-atopic individuals might allow better characterization of the incidence of all upper respiratory tract symptoms
including acute and chronic rhinosinusitis over a 5-year period.
Similarly, a long-term follow-up of a cohort of patients with
nasal polyposis would allow study of the natural history of the
condition.
Identification of environmental modifiers will require prospective assessment of a very large cohort of patients to monitor for
development of disease. While probably impractical for CRS
alone, the trend to development of databases of medical and
genetic information on large populations such as the UK
BioBank initiative may eventually offer populations for this
research.
14-2 Beyond infection: New roles for bacteria
It is increasingly recognised that bacteria may play a role in the
chronic inflammation of CRS. Among others, Staphylococcus
aureus has been specifically implicated, with possible persistence
favoured by bacterial biofilms. In the light of this evidence, the
role of bacteria in CRS needs to further explored in at least three
areas.
1. Host factors favouring persistence of bacterial colonisation
need to be better characterised.
2. The relative importance of biofilms and intracellular S. aureus
in the development and persistence of CRS must be assessed
3. The role of S. aureus in development or persistence of CRS
via postulated staphylococcal enterotoxins stimulating T-cells
directly via a superantigenic mechanism needs to be validated.
14-3 Host response

Further studies into the mechanisms leading to the development
of CTRS need to be identified. Events occurring at the level of
the epithelium including non-specific defences such as innate
immunity need better description and offer potential targets for
therapy.
14-4 Genetics
Finally, pathogenesis of CRS may be better explored with
research techniques taken from the growing field of genetics.
Population association studies may allow detection of polymorphisms in genes in individuals suffering from CRS. Studies of
candidate genes in currently known pathways may allow identification of specific genetic polymorphisms in the different steps of
the pathways, while whole genome scans probing the entire
genome offer the hope of identification of novel genes not suspected of being implicated.
Studies of gene expression in biopsy samples will help identify
differential gene activation in different disease states and following different courses of therapy. Both of these offer the hope for
development of tests allowing better differentiation of disease
states and targeted therapy, with the tantalizing promise of identification of new drug targets not presently exploited.
These studies will require a cohort of investigators trained in
these new techniques and development of multidisciplinary
groups to collect and exploit the large populations required for
these studies. Multinational collaborative initiatives will have to
be initiated to collect the large sample sizes of affected individuals required for this work.
14-5 Clinical trials
Although much work has been recently been done on chronic rhinosinusitis and nasal polyps this work needs to be validated in
terms of its clinical impact. Our understanding needs to translate
into therapy for disease and experimental hypotheses need to verify by appropriate clinical trials. The following suggestions should
highlight some areas of interest for further investigation.
1. Areas that have been identified need to be targeted with specific therapies. In particular, means of targeting biofilms, reducing S. aureus colonisation and of modulating response to S.
aureus enterotoxins need to be developed and assessed by
means of well-designed clinical trials.
2. Emerging therapies need to be assessed critically in order to
determine which ones are effective and in which settings. There
is an urgent need for randomized placebo controlled trials to
study the effect of antibiotics in acute rhinosinusitis, chronic rhinosinusitis and exacerbations of chronic rhinosinusitis. These
106
should be compared with nasal steroids as a single modality of

treatment for these conditions.
3. A well-powered prospective study of the effectiveness of
macrolides in CRS and NP would allow validation of the positive effects suggested by some studies. The role of topical
antibiotic therapy in exacerbations of CRS needs to be performed with well-characterized patients to identify optimal situations for use.
4. In the same fashion, novel therapies introduced over the
coming years should be scrutinised closely prior to widespread
adoption. Specifically, it is hoped that in the future clinicians
will remain vigilant to claims made without the support of
prospective, adequately powered clinical trials.
Supplement 20
5. Surgical management for CRS and NP will probably continue

to play a role in the management of CRS. In the future, rather
than attempting to demonstrate superiority of one therapy over
another, studies should target selected patient populations or situations so as to guide the clinician to a rational use of medical
and/or surgical therapy as part of a comprehensive treatment
plan individualised to stage of disease and patient needs.
6. Most QoL and symptom-specific questionnaires have been
designed for a North American population and need to be validated for European patients.
7. The relationship between the upper and lower respiratory tract
needs further investigation and will offer further insight into
pathophysiology of inflammation and therapeutic possibilities.
107
15. Glosarry terms

Acute non-viral rhinosinusitis (ARS): an episode of sudden onset
with an increase of symptoms after 5 days or persistent symptoms after 10 days with less than 12 weeks duration.
Acute viral rhinosinusitis: an episode of sudden onset with duration of symptoms for less than 10 days
Common cold: Acute viral rhinosinusitis
Chronic rhinosinusitis (CRS): a condition lasting for >12 weeks,
comprising two or more symptoms one of which should be
either nasal blockage/obstruction/congestion or nasal discharge
May occur with or without polyps
Cacosmia: awareness of an unpleasant smell, often rotten or
faeculent
Cobblestoned: an irregular bumpy mucosal surface usually postsurgery for polyps
Conventional surgery: a range of operations which predated endoscopic sinus surgery eg polypectomy, inferior meatal antrostomy,
Caldwell-Luc operation, Denkers procedure, external fronto-ethmoidectomy
Middle meatal antrostomy: an opening into the maxillary sinus

thourgh the lateral wall of the middle meatus
Mucopurulent secretion: a mixture of opaque and discoloured
mucus which is not frank pus
Orbital complications:
Ecchymosis: an area of discoloration beneath the skin secondary
to bleeding
Enophthalmos: abnormal retraction of the eyeball into the socket
Myospherulosis: granulomatous foreign body reaction in soft tissues due to extravasation of paraffin or oil
Orbital emphysema: the presence of air within the soft tissues of
the eye
Periorbital cellulitis: inflammation of the eyelid and conjunctiva
Ostiomeatal complex: that area of the middle meatus into which
the maxillary, anterior ethmoid and frontal sinuses drain
Pansinustis: involvement of all paranasal sinuses, usually demonstrated radiologically
Pathogen: any organism capable of producing disease
Rhinitis medicamentosa: a condition associated with use of
intranasal decongestants in which the nasal mucosa undergoes
atrophy
Endonasal surgery: any surgery performed through the nose

Functional surgery: an operation which aims to restore function
eg restitution of mucocilary clearance, improvement in olfaction
Iatrogenic: a condition induced unintentionally by a physician,
usually by a therapeutic action
Local corticosteroid: topical intranasal instillation of a corticosteroid preparation
Middle meatus: that area of the lateral wall of the nose lying lateral to the middle turbinate
Rhinorrhoea: any discharge from the nose. May run from the
front of the nose (anterior) or into the back (posterior or postnasal discharge)
Rhinosinusitis: inflammation of the nose and paranasal sinuses
Simple polypectomy: surgical removal of polyps from the nasal
cavity without additional surgery on the paranasal sinuses
Treatment:
short term treatment: usually 2 weeks or less
long-term treatment: usually 12 weeks or longer
108
Supplement 20
16. Information on QOL instruments:

16-1 General health status instruments:
16-2 Disease specific health status instruments:
SF-36: www.sf-36.org
Euro-QOL: www.euroqol.org
SF-12: derived from the SF-36: www.sf-36.org
Quality of Well-Being Scale: jharvey@ucsd.edu
Glasgow Benefit Inventory:
www.ihr.mrc.ac.uk/scottish/products/ghsq.php
Mc-Gill pain questionnaire: Ronald Melzack: Department
of Psychology, McGill University, 1205 Dr. Penfield
Avenue, Montreal, Que. H3A 1B1, , Canada
RSOM-31: Jay Piccirillo: piccirij@msnotes.wustl.edu

SNOT-20: derived from the RSOM-31: Jay Piccirillo: piccirij@msnotes.wustl.edu
SNOT-16: derived from the SNOT-20: Eric Anderson,
Department of Otolaryngology-Head and Neck Surgery,
University of Washington School of Medicine, Box 356515,
Seattle, WA 98195-6515, USA
RSDI: Michael Benninger, Department of OtolaryngologyHead and Neck Surgery, Henry Ford Hospital, 2799 W
Grand Blvd, Detroit, MI 48202, USA
RQLQ: www.qoltech.co.uk
RSUI: D.A. Revicki: revicki@medtap.com
SN-5: David Kay: davidkay@pol.net
RhinoQol: Steven Atlas: satlas@partners.org
109
17. Survey of published olfactory tests

Author(s)
Year
Test name
Test-Time
Country
Sample size
Cain
1983
1988
1989
CCCRC
35 min
USA
>700
Doty et al (1084)
1984
(a,b)
1985
UPSIT
15 min
USA
>3000
Wright (1085)
1987
Odourant
Confusion
15 min
USA
Kurtz et al (1086)
2001
Matrix
(OCM)
Hendriks (1087)
1988
GITU
Netherlands
Corwin (1088)
1989
1992
YN-OIT
USA
Takagi (1089)
1989
T&T
Olfactometer
Japan
Anderson et al
1992
SDOIT
Eloit and Trotier
1994
(1081-1083)
Test retest
Subject differences
Method
Age, gender,
diseases, olfactory
disorders.
1/ Threshold. Nbutanol.
2AFC 4-correct-in-arow method. Separate
nostrils. Odours in
squeeze bottles
2/Identification. 10
odours (score on &+1).
Forced choice from
20 (or 16) descriptors.
Odours in jars. Separate nostrils. Feedback.
Age, gender, culture,

smoker, disease,
olfactory disorder,
malingering.
Identification of 40
encapsuated odours.
4AFC. Scratch-andsniff- technique
480
Disease.
odours each presented
once (100 stimuli
or 121 if a blank
is added). Forced
choice from list of 10
names. Pattern of
odorant identification
and misidentification.
221
Age, gender, olfactory disorders.
or 36 odours. Forced
choice either from 4
alternatives or from a
list of 24 for 18 odours
to identify.
Everyday life odours.
Odours in jars.
Age, disease
Based on 20 UPSIT
odours. Yes or no
matching of a descriptor to a proposed
odour.
>1000
Olfactory disorders.
Thresholds of detection and recognition

for 5 odorants. Odours
on slips of filter papers.
Separate nostrils.
USA
Young
children
Age.
Identification of
10 odours. Forced
choice using an array
of 20 visual stimuli.
Odours in jars.
France
84
Olfactory disorder,
disease.
Odours in bottles.
1/Threshold to 5
odorants.
2/Identification of 6
odorants.
Odours in bottles.
USA
Europe
Asia
>3000
Age, gender, olfactory disorders.
encapsulated odours.
4AFC. Scratch and
sniff technique.
r=0.981
(1090)
Doty et al (1091, 1092)
1995
1996
CC-SIT
MOD-SIT
5 min
r=0.71
110
Supplement 20
Author(s)
Year
Kobal et al (1093)
1996
Robson et al (1094)
1996
Hummel et al (1095)
Kobal et al (1096)
1997
Test name
Test-Time
Country
Sample size
Test retest
Subject differences
Method
5 min
Germany
152
r=0.73
Gender, olfactory
disorder, age.
Identification of
7 odours in pens.
Forced choice from 4
alternatives.
Combined
olfactory
test
UK and New
Zealand
227
Olfactory disorder.
1/Threshold for nbutanol. Odours in

plastic containers.
2/Identification of
9 odours. 4AFCE.
Odours in jars.
SniffinSticks
Germany,
>1000
Age, olfactory
disorder.
Odours in pens.
2000
Switzerland,
Austria,
Australia,
Italy,
USA
Davidson and
Murphy (1097)
1997
AST
Ahlskog et al (1098)
1998
CA-UPSIT
Nordin (1099)
1998
SOIT
Kremer et al (1100)
1998
McCaffrey et
al (1101)
2000
PST
Kobal et al (1102)
2001
Random
test
Hummel et al (1103)
2001
Four-minute odour
identification test
Cardesin et al.,
2006
Barcelona
Smell
Test - 24
(BAST-24)
(1104)
r=0.72
5 min
1/Threshold for nbutanol. Triple forced

choice paradigm. Single staircase method.
2/Discrimination:
16 odorant triplets.
Identify the pen with
the different smell.
Forced choice.
3/Identification: 16
odours. 4AFC
USA
100
Olfactory disorder.
Detection of isopropanol. Measure as

distance from nose.
Guamanian
Chamorro
57
Neuro-degnerative
disease.
Educational level.
4AFC. Scratch-andsniff technique.
15 min
Sweden
Finland
>600
Age, gender, olfactory disorder.
odours in bottles.
4AFC
4 min
Germany
Netherlands
>200
Hyposmia.
6 aromas sprayed into

open mouth. Odours
in nasal sprays.
USA
40
Discrimination between Alzheimers

dementia and major
depression.
Identification of 3
4AFC. Scratch-andsniff technique.
10 min
Germany
273
r=0.71
Gender, olfactory
disorder.
Labelling of 16
concentrations of two
odorants randomly
presented.
4 min
Germany
1,012
r=0.78
Age, olfactory
disorder.
Identification of
12 odours. 4AFC.
Odours in pens.
Spanish
120
r=0.79
24 odours scoring
smell detection, identification, and forced
choice
111
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Corrected version: October 11, 2007

Rhinology supplement 20 EPOS 2007

European Position Paper on

Marek Kowalski, Department of Immunology, Rheumatology

European Position Paper on Rhinosinusitis and Nasal Polyps 2007

Definition of rhinosinusitis and nasal polyps

Chronic rhinosinusitis with or without nasal polyps

Epidemiology and predisposing factors

Inflammatory mechanisms in acute and chronic

Complications of rhinosinusitis and nasal polyps

Special considerations: Rhinosinusitis in children

Chronic rhinosinusitis with or without nasal polyps

Socio-economic cost of chronic rhinosinusitis and

Outcomes measurements in research

Evidence based schemes for diagnostic and treatment

14 Research needs and priorities

16 Information on QOL instruments:

Survey of published olfactory tests

European Position Paper on Rhinosinusitis and Nasal Polyps 2007

evidence from meta-analysis of randomised controlled trials

Table 1-2. Strength of recommendation

directly based on category I evidence

This revision is intended to be a state-of-the art review for the

2. Definition of rhinosinusitis and nasal polyps

2-2-2 Severity of the disease

A VAS > 5 affects patient QOL (14).

2-2 Clinical definition

2-3 Definition for use in epidemiology studies/General Practice

2-2-1 Clinical definition of rhinosinusitis/nasal polyps

Acute rhinosinusitis (ARS) is defined as:

European Position Paper on Rhinosinusitis and Nasal Polyps 2007

Common cold/ acute viral rhinosinusitis is defined as:

This definition accepts that there is a spectrum of disease in

3. Chronic rhinosinusitis with or without nasal polyps

Figure 3-1. The spectrum of chronic rhinosinusitis and nasal polyps

Nasal polyps appear as grape-like structures in the upper nasal

European Position Paper on Rhinosinusitis and Nasal Polyps 2007

The reason why polyps develop in some patients and not in

4. Epidemiology and predisposing factors

condition. For example in the Cochrane Review on antibiotics

4-2 Acute bacterial rhinosinusitis.

4-3-2 Ciliary impairment

European Position Paper on Rhinosinusitis and Nasal Polyps 2007

Also in animal experiments it was shown that shortly after

Radiologic studies are unhelpful in unravelling the correlation

4-3-5 Other risk factors : ventilation, naso-gastric tube

The paucity of accurate epidemiologic data on CRS with or

4-5-1 Ciliary impairment

Interestingly, the prevalence rate of CRS was substantially

It has been postulated (97) that swelling of the nasal mucosa in

European Position Paper on Rhinosinusitis and Nasal Polyps 2007

atric CRS section (see Chapter 7-6). However, dysfunction of

4-5-5 Genetic factors

mucosa, indirect hormonal effects like vascular changes may

European Position Paper on Rhinosinusitis and Nasal Polyps 2007

chronic rhinosinusitis was proposed to replace previously used

4-5-10 Environmental factors

4-5-11 Iatrogenic factors

patients with CRS with NP not seeking medical attention,

From autopsy studies, a prevalence of 2% has been found

pared to 3.9% in a control population (185). On the other hand,

European Position Paper on Rhinosinusitis and Nasal Polyps 2007

found to be associated with NP, such susceptibility can be